蛋白激酶C-α在重组人内皮抑素抑制兔耳创面愈合和血管增生中的作用
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摘要
背景与目的内皮抑素(ES)作为最重要的血管生成抑制因子,已被广泛应用于抗肿瘤血管生成治疗。既往研究表明ES可抑制瘢痕增生,但目前尚未见局部外用ES对创面愈合影响及蛋白激酶C(PKC)-a是否介导其作用的研究报道。本实验探讨PKC-a在ES调控创面愈合及血管增生中的信号作用。
材料与方法选用健康成年新西兰大耳白兔36只,雌雄不限,体重2.0-2.5kg。所有动物适应性饲养1周,3%戊巴比妥钠(1.0ml/kg)耳缘静脉麻醉后,分别在每只兔耳腹侧做4个直径为10.0mm,间距15.0mm的全层皮肤缺损创面。将36只大耳白兔随机分为6组：Rh-ES组、PMA组、Go6983组、Rh-ES+PMA组、Rh-ES+Go6983组和PBS对照组,每组48个创面,分别湿敷Rh-ES (10μg/ml)、 PMA (10nM)、Go6983(1nM)、Rh-ES+PMA (10μg/ml+10nM)、Rh-ES+Go6983(10μg/ml+1nM)和等量的PBS液。于伤后3d、7d、11d和上皮化(12d-16d)时观察创面愈合情况,记录创面愈合时间和创面愈合率,并切取创面标本行免疫组化染色检测CD34、PKC-a表达并计算微血管密度(MVD)。所有数据用均数±标准差(x±s)表示。采用SPSS17.0软件包进行统计处理：方差齐性时多组间均数比较采用方差分析,组间两两比较采用LSD法；方差不齐时采用Kruskal-Wallis检验,P<0.05为差异有统计学意义。
结果1.创面愈合时间：各组间创面愈合时间存在显著差异(F=9.241,P=0.000)。Rh-ES组、Go6983组、Rh-ES+G66983组愈合时间分别为(14.33±1.15)d、(14.58±1.24)d、(15.08±1.08)d,较对照组(13.36±1.21)d延长(P<0.05),而PMA组愈合时间(12.36±0.67)d缩短(P＜0.05), Rh-ES+PMA组(13.45±1.13)d与对照组相似(P＞0.05)。Rh-ES+Go6983组愈合时间较Rh-ES组延长(P<0.05),而Rh-ES+PMA组缩短(P<0.05)。
2.创面愈合率：伤后第3d, Rh-ES+Go6983组创面愈合率低于PMA组和对照组(P<0.05),其余各组间创面愈合率无差异(P>0.05)。伤后第7d和第11d,Rh-ES组、Go6983组、Rh-ES+Go6983组创面愈合率低于对照组(P<0.05),但两两之间无差异(P>0.05)；PMA组创面愈合率较其余各组增加(P<0.05)。Rh-ES+PMA组各时间点创面愈合率与对照组相似(P>0.05)。
3.MVD：伤后第3d, Rh-ES+Go6983组MVD低于对照组(P<0.05),其余各组与对照组相似(P>0.05)。自伤后第7d起Rh-ES组和Go6983组MVD低于对照组(P<0.05)而PMA组高于对照组(P<0.05),Rh-ES+PMA组MVD高于Rh-ES组、Go6983组和Rh-ES+Go6983组(P<0.05),但与对照组无差异(P>0.05),Rh-ES+Go6983组MVD低于对照组(P<0.05)。
4. PKC-α表达：Rh-ES组各时间点PKC-a表达与对照组无差异(P>0.05)。自伤后第7d起PMA组和Rh-ES+PMA组PKC-a表达均高于其余各组(P<0.05),而Go6983组和Rh-ES+Go6983组PKC-a表达均低于其余各组(P<0.05),但PMA组和Rh-ES+PMA组、Go6983组和Rh-ES+Go6983组组间无差异(P>0.05)。
结论1.内皮抑素可显著降低肉芽组织微血管密度,并延迟创面愈合。2.PKC-a可能不介导内皮抑素处理创面抑制血管增生的作用。3.PKC活化剂(PMA)促进创面愈合,PKC抑制剂(G66983)延迟创面愈合。
Background and objective Endostatin(ES),as the most important angiogenesis inhibitor,has been widely used in anti-tumor angiogenesis therapy. Previous study showed that ES can inhibit scar hyperplasia,but it lack of the experimental report about the effect of local application of ES on wound healing and whether protein kinase C(PKC)-alpha involved in this process at present. This study is to investigate the roles of PKC-alpha in the process of angiogenesis of ES on wound healing.
Materials and methods Thirty-six adult, healthy New Zealand white rabbits had been chosed weighing from2.0to2.5kg,without thinking of sex. Each rabbit was housed in a separate cage and was feeded for one week. After anesthetization with sodium pentobarbital through the auricular vein (1.Oml/kg body weight),four standardized full-thickness skin wounds of10.0mm in diameter extending to the cartilage were made on the ventral side of each rabbit ear. All the rabbits were randomly divided in to the Rh-ES treated group(10μg/ml), the PMA treated-group(10nM),the Go6983treated-group(1nM), the Rh-ES+PMA treated-group(10μg/ml+10nM),the Rh-ES+Go6983treated-group(10μg/ml+1nM) and the control group (PBS treatment). On the3rd,7th,11th post-wound day (PWDs) and epithelization(12th-16th PWDs),the wound healing rate and wound healing time were recorded and the wounds tissues were collected.The microvessel density(MVD) of wound tissues was counted according to the result of CD34immunohistochemistry and the expressions of PKC-alpha were determined.The data,expressed with(x±s), were assessed by the analysis of variance when homogeneity of variance among groups was satisfied, otherwise by the Kruskal-Wallis Test,and their further multiple comparison by LSD(least significant different) method. Data were analyzed using SPSS17.0for Windows, p<0.05was considered statistically significant.
Results
1. The wound healing time:There was significant differences in wound healing time among6groups (F=9.241, P=0.000).The wound healing time of Rh-ES-treated group(14.33±1.15)d, Go6983treated-group (14.58±1.24)d, Rh-ES+Go6983treated-group(15.08±1.08)d were longer than control group[(13.36±1.21)d, P＜0.05], while PMA treated-group(12.36±0.67)d was shorter(P＜0.05). The wound healing time of Rh-ES+PMA treated-group(13.45±1.13)d had no difference compared with control group(P>0.05).The wound healing time of Rh-ES+Go6983treated-group were longerer than Rh-ES treated-group(P<0.05),while Rh-ES+PMA treated-group was shorter (P＜0.05).
2. The wound healing rate:The wound healing rate of Rh-ES+Go6983treated-group was lower than PMA treated-group and control group(P＜0.05), and other groups' wound healing rates had no different on3rd PSDs(P>0.05).Compared with control group, the wound healing rate of Rh-ES treated group,Go6983treated-group, Rh-ES+Go6983treated-group were decreased signifieantly on the7th and11th PWDs (P＜0.05),but there was no difference between the any of two out of three groups(P＞0.05);While the wound healing rate of PMA treated-group was inereased significantly compared with other groups(P＜0.05). And the wound healing rate had no difference between Rh-ES+PMA treated-group and control group in any PWDs(P＞0.05).
3. Microvessel density (MVD):The MVD of Rh-ES+Go6983treated-group was lower than control group(P＜0.05), and other groups had no difference compared with control group on3rd PSDs(P＞0.05). Since the7th PWDs, the MVD of Rh-ES treated group and Go6983treated-group were lower than control group (P＜0.05),while PMA treated-group were higher than control group(P＜0.05). The MVD of Rh-ES+PMA treated-group was higher than Rh-ES treated group,Go6983treated-group and Rh-ES+Go6983treated-group,but had no difference compared with control group at the same time (P>0.05). The MVD of Rh-ES+Go6983treated-group was lower than control group (P＜0.05).
4. Expression of PKC-alpha:There was no differences to the expression of PKC-alpha in Rh-ES treated-group compared with control group in any PWDs(P＞0.05). Since the7th PSDs,the expression of PKC-alpha increased significantly in all groups.The expression levels of PKC-alpha was higher in PMA treated-group or Rh-ES+PMA treated-group than in other groups(P＜0.05),while lower in Go6983treated-group or Rh-ES+G66983treated-group than in other groups (P＜0.05). There was no significant difference between PMA treated-group and Rh-ES+PMA treated-group,as well as Go6983treated-group and Rh-ES+Go6983treated-group(P>0.05).
Conclusions1. Endostatin might reduce the microvessel density of the granulation tissue and delay wound healing.
2. PKC-alpha might not mediate the anti-angiogenesis effect of endostatin on wound healing.
3.PKC activator (PMA) might promote wound healing, and PKC inhibitor (Go6983) was just the opposite.
材料与方法选用健康成年新西兰大耳白兔36只,雌雄不限,体重2.0-2.5kg。所有动物适应性饲养1周,3%戊巴比妥钠(1.0ml/kg)耳缘静脉麻醉后,分别在每只兔耳腹侧做4个直径为10.0mm,间距15.0mm的全层皮肤缺损创面。将36只大耳白兔随机分为6组：Rh-ES组、PMA组、Go6983组、Rh-ES+PMA组、Rh-ES+Go6983组和PBS对照组,每组48个创面,分别湿敷Rh-ES (10μg/ml)、 PMA (10nM)、Go6983(1nM)、Rh-ES+PMA (10μg/ml+10nM)、Rh-ES+Go6983(10μg/ml+1nM)和等量的PBS液。于伤后3d、7d、11d和上皮化(12d-16d)时观察创面愈合情况,记录创面愈合时间和创面愈合率,并切取创面标本行免疫组化染色检测CD34、PKC-a表达并计算微血管密度(MVD)。所有数据用均数±标准差(x±s)表示。采用SPSS17.0软件包进行统计处理：方差齐性时多组间均数比较采用方差分析,组间两两比较采用LSD法；方差不齐时采用Kruskal-Wallis检验,P<0.05为差异有统计学意义。
结果1.创面愈合时间：各组间创面愈合时间存在显著差异(F=9.241,P=0.000)。Rh-ES组、Go6983组、Rh-ES+G66983组愈合时间分别为(14.33±1.15)d、(14.58±1.24)d、(15.08±1.08)d,较对照组(13.36±1.21)d延长(P<0.05),而PMA组愈合时间(12.36±0.67)d缩短(P＜0.05), Rh-ES+PMA组(13.45±1.13)d与对照组相似(P＞0.05)。Rh-ES+Go6983组愈合时间较Rh-ES组延长(P<0.05),而Rh-ES+PMA组缩短(P<0.05)。
2.创面愈合率：伤后第3d, Rh-ES+Go6983组创面愈合率低于PMA组和对照组(P<0.05),其余各组间创面愈合率无差异(P>0.05)。伤后第7d和第11d,Rh-ES组、Go6983组、Rh-ES+Go6983组创面愈合率低于对照组(P<0.05),但两两之间无差异(P>0.05)；PMA组创面愈合率较其余各组增加(P<0.05)。Rh-ES+PMA组各时间点创面愈合率与对照组相似(P>0.05)。
3.MVD：伤后第3d, Rh-ES+Go6983组MVD低于对照组(P<0.05),其余各组与对照组相似(P>0.05)。自伤后第7d起Rh-ES组和Go6983组MVD低于对照组(P<0.05)而PMA组高于对照组(P<0.05),Rh-ES+PMA组MVD高于Rh-ES组、Go6983组和Rh-ES+Go6983组(P<0.05),但与对照组无差异(P>0.05),Rh-ES+Go6983组MVD低于对照组(P<0.05)。
4. PKC-α表达：Rh-ES组各时间点PKC-a表达与对照组无差异(P>0.05)。自伤后第7d起PMA组和Rh-ES+PMA组PKC-a表达均高于其余各组(P<0.05),而Go6983组和Rh-ES+Go6983组PKC-a表达均低于其余各组(P<0.05),但PMA组和Rh-ES+PMA组、Go6983组和Rh-ES+Go6983组组间无差异(P>0.05)。
结论1.内皮抑素可显著降低肉芽组织微血管密度,并延迟创面愈合。2.PKC-a可能不介导内皮抑素处理创面抑制血管增生的作用。3.PKC活化剂(PMA)促进创面愈合,PKC抑制剂(G66983)延迟创面愈合。
Background and objective Endostatin(ES),as the most important angiogenesis inhibitor,has been widely used in anti-tumor angiogenesis therapy. Previous study showed that ES can inhibit scar hyperplasia,but it lack of the experimental report about the effect of local application of ES on wound healing and whether protein kinase C(PKC)-alpha involved in this process at present. This study is to investigate the roles of PKC-alpha in the process of angiogenesis of ES on wound healing.
Materials and methods Thirty-six adult, healthy New Zealand white rabbits had been chosed weighing from2.0to2.5kg,without thinking of sex. Each rabbit was housed in a separate cage and was feeded for one week. After anesthetization with sodium pentobarbital through the auricular vein (1.Oml/kg body weight),four standardized full-thickness skin wounds of10.0mm in diameter extending to the cartilage were made on the ventral side of each rabbit ear. All the rabbits were randomly divided in to the Rh-ES treated group(10μg/ml), the PMA treated-group(10nM),the Go6983treated-group(1nM), the Rh-ES+PMA treated-group(10μg/ml+10nM),the Rh-ES+Go6983treated-group(10μg/ml+1nM) and the control group (PBS treatment). On the3rd,7th,11th post-wound day (PWDs) and epithelization(12th-16th PWDs),the wound healing rate and wound healing time were recorded and the wounds tissues were collected.The microvessel density(MVD) of wound tissues was counted according to the result of CD34immunohistochemistry and the expressions of PKC-alpha were determined.The data,expressed with(x±s), were assessed by the analysis of variance when homogeneity of variance among groups was satisfied, otherwise by the Kruskal-Wallis Test,and their further multiple comparison by LSD(least significant different) method. Data were analyzed using SPSS17.0for Windows, p<0.05was considered statistically significant.
Results
1. The wound healing time:There was significant differences in wound healing time among6groups (F=9.241, P=0.000).The wound healing time of Rh-ES-treated group(14.33±1.15)d, Go6983treated-group (14.58±1.24)d, Rh-ES+Go6983treated-group(15.08±1.08)d were longer than control group[(13.36±1.21)d, P＜0.05], while PMA treated-group(12.36±0.67)d was shorter(P＜0.05). The wound healing time of Rh-ES+PMA treated-group(13.45±1.13)d had no difference compared with control group(P>0.05).The wound healing time of Rh-ES+Go6983treated-group were longerer than Rh-ES treated-group(P<0.05),while Rh-ES+PMA treated-group was shorter (P＜0.05).
2. The wound healing rate:The wound healing rate of Rh-ES+Go6983treated-group was lower than PMA treated-group and control group(P＜0.05), and other groups' wound healing rates had no different on3rd PSDs(P>0.05).Compared with control group, the wound healing rate of Rh-ES treated group,Go6983treated-group, Rh-ES+Go6983treated-group were decreased signifieantly on the7th and11th PWDs (P＜0.05),but there was no difference between the any of two out of three groups(P＞0.05);While the wound healing rate of PMA treated-group was inereased significantly compared with other groups(P＜0.05). And the wound healing rate had no difference between Rh-ES+PMA treated-group and control group in any PWDs(P＞0.05).
3. Microvessel density (MVD):The MVD of Rh-ES+Go6983treated-group was lower than control group(P＜0.05), and other groups had no difference compared with control group on3rd PSDs(P＞0.05). Since the7th PWDs, the MVD of Rh-ES treated group and Go6983treated-group were lower than control group (P＜0.05),while PMA treated-group were higher than control group(P＜0.05). The MVD of Rh-ES+PMA treated-group was higher than Rh-ES treated group,Go6983treated-group and Rh-ES+Go6983treated-group,but had no difference compared with control group at the same time (P>0.05). The MVD of Rh-ES+Go6983treated-group was lower than control group (P＜0.05).
4. Expression of PKC-alpha:There was no differences to the expression of PKC-alpha in Rh-ES treated-group compared with control group in any PWDs(P＞0.05). Since the7th PSDs,the expression of PKC-alpha increased significantly in all groups.The expression levels of PKC-alpha was higher in PMA treated-group or Rh-ES+PMA treated-group than in other groups(P＜0.05),while lower in Go6983treated-group or Rh-ES+G66983treated-group than in other groups (P＜0.05). There was no significant difference between PMA treated-group and Rh-ES+PMA treated-group,as well as Go6983treated-group and Rh-ES+Go6983treated-group(P>0.05).
Conclusions1. Endostatin might reduce the microvessel density of the granulation tissue and delay wound healing.
2. PKC-alpha might not mediate the anti-angiogenesis effect of endostatin on wound healing.
3.PKC activator (PMA) might promote wound healing, and PKC inhibitor (Go6983) was just the opposite.
引文
[1]Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM.Isolation of putative progenitor endothelial cells for angiogenesis [J].Science,1997,275(5302):964-967.
[2]O Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J.Endostatin:an endogenous inhibitor of angiogenesis and tumor growth [J].Cell,1997,88(2):277-285.
[3]Folkman J. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action[J]. Exp Cell Res,2006,312(5):594-607.
[4]李虎,李小静,宁金龙,孟刚,高凤山,董继英.血管生长抑制因子对兔耳增生性瘢痕的作用及意义[J].中华医学美学美容杂志,2007,13(4)：237-239.
[5]王棚,薛斌,江黎珠,雷彬,宋鹏宇,丁云鹏,李晶,蒋娟.重组人血管内皮抑制素可抑制兔耳增生性瘢痕[J].中国组织工程研究与临床康复,2011,15(46)：8689-8692.
[6]Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing [J].FASEB J,2000,14(15):2373-2376.
[7]Michaels J 5th, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration [J]. Wound Repair Regen,2005,13(5):506-512.
[8]Petersen W, Pufe T, Starke C, Fuchs T, Kopf S, Raschke M, Becker R, Tillmann B. Locally applied angiogenic factors-a new therapeutic tool for meniscal repair [J]. Ann Anat,2005,187(5-6):509-519.
[9]Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing [J]. J Surg Res,2000,91(1):26-31.
[10]Mundhenke C, Thomas JP, Wilding G, Lee FT, Kelzc F, Chappell R, Neider R, Sebree LA, Friedl A. Tissue examination to monitor antiangiogenic therapy:a phase I clinical trial with endostatin [J]. Clin Cancer Res,2001,7(11):3366-3374.
[11]Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while over expression of its endostatin domain leads to delayed healing [J]. Matrix Biol,2008,27(6):535-546.
[12]Azzi A, boscoboinik D, Hensey C. The protein kinase C family [J]. Eur J Biochem,1992, 208(3):547-557.
[13]张丹.蛋白激酶C亚型与癌肿[J].辽宁医学杂志,2009,32(5)：265-268.
[14]Parekh DB, ZiegIer W, Parker PJ. Multiple pathways control protein kinase C phosphoryIation [J]. Embo J,2000,19(4):496-503.
[15]向敏,徐永健.周期蛋白D1在香烟烟雾致人肺动脉平滑肌细胞增殖中作用及其与蛋白激酶C-α关系的研究[D].华中科技大学博士学位论文,2010,5.
[16]Zhou LY, Disatnik M, Herron GS, Mochly-Rosen D, Karasek MA. Differential activation of protein kinase C isozymes by phorbol ester and collagen in human skin microvascular endothelial cells [J]. J Invest Dermatol,1996,107(2):248-252.
[17]Wellner M, Maasch C, Kupprion C, Lindschau C, Luft FC, Haller H. The proliferative effect of vascular endothelial growth factor requires protein kinase C-alpha and protein kinase C-zeta[J].Arterioscler Thro -mb Vasc Biol,1999,19(1):178-185.
[18]Yasunari K, Kohno M, Kano H, Minami M, Yoshikawa J. Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose[J]. Hypertension,2000,35(5):1092-1098.
[19]Tang S, Morgan KG, Parker C, Ware JA. Requirement for protein kinase C theta for cell cycle progression and formation of actin stress fibers and filopodia in vascular endothelial cells [J]. J Biol Chem,1997,272(45):28704-28711.
[20]Daviet I, Herbert JM, Maffrand M. Tumor-promoting phorbol esters stimulate bovine cerebral cortex capillary endothelial cell growth in vitro [J]. Biochem Biophys Res Commun, 1989,158(2):584-589.
[21]Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct alpha v Integrins[J].Science,1995,270(5241):1500-1502.
[22]Ilan N, Mahooti S, Madri JA.Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis [J]. J Cell Sci,1998,111 (Pt 24):3621-3631.
[23]Doctrow SR, Folkman J. Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens [J]. J Cell Biol,1987,104(3): 679-687
[24]Kosaka C, Sasaguri T, Ishida A, Ogata J. Cell cycle arrest in the G2 phase induced by phorbol ester and diacylglycerol in vascular endothelial cells [J]. Am J Physiol,1996,270(lPtl) C170-C178.
[25]Gailit J, Clark RA. Wound repair in the context of extracellular matrix [J]. Curr Opin Cell Biol,1994,6(5):717-725.
[26]Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D. The alpha isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells [J]. Mol Biol Cell,2000,11(3):1077-1092.
[27]Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication [J]. J Cell Biol,2000,149(7):1503-1512.
[28]Richards TS, Dunn CA, Carter WG, Usui ML, Olerud JE, Lampe PD. Richards TS, Dunn CA, Carter WG, et al. Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368[J]. J Cell Biol,2004,167(3):555-562.
[29]Alt A, Ohba M, Li L, Gartsbein M, Belanger A, Denning MF, Kuroki T, Yuspa SH, Tennenbaum T. Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment [J]. Cancer Res,2001,61(11):4591-4598
[30]Rabinovitz I, Tsomo L, Mercurio AM. Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes [J]. Mol Cell Biol,2004,24(10):4351-4360
[31]Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Epidermal growth factor induces fibronectin expression in human dermal fibroblasts via protein kinase C delta signaling pathway[J]. J Invest Dermatol,2004,122(6):1390-1398.
[32]Zhang XF, Guo SZ, Lu KH, Li HY, Li XD, Zhang LX, Yang L. Different roles of PKC and PKA in effect of interferon-y on proliferation and collagen synthesis of fibroblasts[J]. Acta Pharmacol Sin,2004,25(10):1320-1326.
[33]Chida K, Hara T, Hirai T, Konishi C, Nakamura K, Nakao K, Aiba A, Katsuki M, Kuroki T. Disruption of protein kinase C eta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis[J]. Cancer Res,2003,63(10):2404-2408.
[34]Leask A, Shi-Wen X, Khan K, Chen Y, Holmes A, Eastwood M, Denton CP, Black CM, Abraham DJ. Loss of protein kinase C-epsilon results in impaired cutaneous wound closure and myofibroblast function [J]. Cell Sci,2008,121 (Pt20):3459-3467.
[35]张选奋,郭树忠,张琳西,刘凯IFN-y抑制兔耳皮肤伤口愈合和瘢痕增生中蛋白激酶C的活性变化[J].中华整形外科杂志,2006,22(6)：442-444.
[36]时荣,张选奋.皮肤创伤再生和瘢痕愈合中Ⅰ、Ⅲ型胶原和PKC-γ、-λ的差异表达[D].兰州大学硕士学位论文,2012,5.
[37]Li X, Hahn CN, Parsons M, Drew J, Vadas MA, Gamble JR. Role of protein kinase C zeta in thrombin-induced endothelial permeability changes:inhibition by angiopoietin-1[J]. Blood,2004,104(6):1716-1724.
[38]Cardell M, Landsend AS, Eidet J, Wieloch T, Blackstad TW, Ottersen OP. High resolution immunogold analysis reveals distinct subcellular compartmentalization of protein kinase C gamma and delta in rat Purkinje cells [J]. Neuroscience,1998,82(3):709-725.
[39]Shimohama S, Uehara-Kunugi Y, Terai K, Taniguchi T, Kimura J, Saitoh T. Expression of protein kinase C isozymes inprimary neuronal cultures of the rat cerebellum[J]. J Neurosci Res,1991,29(2):261-270.
[40]Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO. Protein kinase C isozymes and the regulation of diverse cell responses [J]. Am J Physiol Lung Cell Mol Physiol,2000,279(3):L429-438.
[41]Lo LW, Cheng JJ, Chiu JJ. Endothelial exposure to hypoxia induces Egr-1 expression involving PKCalpha-mediated Ras/Raf-1/ERK1/2 pathway[J]. J Cell Physiol, 2001,188(3):304-312.
[42]Cheng JJ, Wung BS, Chao YJ, Wang DL. Sequential activation of protein kinase C (PKC)-alpha and PKC-epsilon contributes to sustained Raf/ERK1/2 activation in endothelial cells under mechanical strain [J]. J Biol Chem,2001,276(33):31368-31375.
[43]Mandil R, Ashkenazi E, Blass M, Kronfeld I, Kazimirsky G, Rosenthal G, Umansky F, Lorenzo PS, Blumberg PM, Brodie C. Protein kinase Ca and protein kinase Cδ play opposite roles in the proliferation and apoptosisof glioma cells[J]. Cancer Res,2001,61 (11): 4612-4619.
[44]Ways DK, Kukoly CA, deVente J, Hooker JL, Bryant WO, Posekany KJ, Fletcher DJ, Cook PP, Parker PJ. MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype [J]. J Clin Invest,1995,95(4):1906-1915.
[45]Borner C, Filipuzzi I, Weinstein IB, Imber R. Failure of wild-type or a mutant form of protein kinase C-alpha to transform fibroblasts [J]. Nature,1991,353(6339):78-80.
[46]晏晓明,黄萍.PKC对人角膜基质细胞增殖的影响及对细胞周期的调控作用[A]；第七届全国角膜病及眼表疾病学术会议[C],2003.
[47]Ng T, Shima D, Squire A, Bastiaens PI, Gschmeissner S, Humphries MJ, Parker PJ. PKC alpha regulates betal integrin-dependent cell motility through association and control of integrin trafic [J]. EMBO J,1999,18(14):3909-3923.
[48]Morris DE, Wu L, Zhao LL, Bolton L, Roth SI, Ladin DA, Mustoe TA. Acute and chronic animal models for excessive dermal scarring:quantitative studies[J]. Plast Reconst Surg,1997,100(3):674-681.
[49]柳大烈,李希军,张阳,李玉霞.外源性透明质酸对创面愈合的影响[J].中国修复重建外科杂志,2002,16(4)：256-258.
[50]Pareek G, Shevchuk M, Armenakas NA, Vasjovic L, Hochberg DA, Basillote JB, Fracchia JA.The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density:a possible mechanism for decreased prostatic bleeding in treated patients [J]. J Urol,2003,169(1):20-23.
[51]朱长举,陆旭,朱盛兴,赵永福,马秀现,张水军.灯盏花素对脑死亡巴马小型猪心脏结构、功能及蛋白激酶C表达的影响[J].西安交通大学学报(医学版),2007,28(1)：303-306.
[52]武元元,叶兰萍,张选奋.内皮抑素对新血管形成和皮肤创伤修复的影响.中华实验外科杂志[J].2013,30(3)：467-468.
[53]Schmidt A, Addicks K, Bloch W. Opposite effects of endostatin on different endothelial cells[J].Cancer Biol Ther,2004,3(11):1162-1166.
[54]袁中芳,魏增涛,王晓.重组内皮抑素抑制兔角膜新生血管的实验研究[J].山东大学耳鼻喉眼学报,2006,20(6)：552-554,558.
[55]王西樵,刘英开,宋菲,徐连菊,青春,陆树良.内皮抑素局部注射对兔耳增生性瘢痕的影响[J].上海交通大学学报(医学版),2011,31(12)：1672-1675,1701.
[56]张选奋,郭树忠,张琳西,刘凯TGF-β1对兔耳创面肉芽组织和瘢痕组织蛋白激酶C活性的影响[J].中国美容医学杂志,2004,13(2)：140-142.
[57]Hanauske AR, Sundell K, Lahn M. The role of protein kinase C-alpha (PKC-alpha) in cancer and its modulation by the novel PKC-alpha-specific inhibitor aprinocarsen [J].Curr Pharm Des,2004,10(16):1923-1936.
[58]Nakashima S. Protein kinase Ca (PKCa):Regulation and Biological Function [J]. J Biochem, 2002,132(5):669-675.
[59]Shimamura K, Takashiro Y, Akiyama N, Hirabayashi T, Murayama T. Expression of adhesion molecules by sphingosine 1-phosphate and histamine in endothelial cells[J]. Eur J Pharmacol,2004,486(2):141-150.
[60]万沁,童南伟,刘小菁,吴惠.高糖对血管内皮细胞蛋白激酶Ca和表达及功能的影响[J].中国糖尿病杂志,2007,,15(8)：505-506.
[61]Wang A, Nomura M, Patan S, Ware JA. Inhibition of protein kinase C alpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo [J]. Circ Res,2002,90(5):609-616.
[62]Chandrasekher G, Bazan NG, Bazan HE.Selective changes in protein kinase C (PKC) isoform expression in rabbit corneal epithelium during wound healing. Inhibition of corneal epithelial repair by PKCalpha antisense [J]. Exp Eye Res,1998,67(5):603-610.
[63]Bokhari SM, Zhou L, Karasek MA, Paturi SG, Chaudhuri V. Regulation of skin microvasculature angiogenesis, cell migration, and permeability by a specific inhibitor of PKC alpha [J]. J Invest Dermatol,2006,126(2):460-467.
[64]Lin N, Bazan HE. Protein kinase C subspecies in rabbit corneal epithelium:increased activity of alpha subspecies during wound healing [J]. Curr Eye Res,1992,11(9):899-907.
[1]周明,王远东,凌国辉, 程国华,韩国栋,邹青峰,王建,谭小军,杨嵘皓,卢家玲.重组人血管内皮抑素与化疗联合治疗肺癌的时序性研究[J].中华实验外科杂志,2011,28：1743-1745.
[2]吕纯业,邵成浩,胡先贵,张怡杰,刘瑞,金钢.转染人Endostatin基因对胰腺癌SW1990 细胞增殖、凋亡及血管内皮生长因子表达的影响[J].中华实验外科杂志,2007,24：826-828.
[3]Reis RC, Schuppan D, Barreto AC, Bork JP, Hassler G, Coelho-Sampaio T. Endostatin competes with bFGF for binding to heparin-like glycosaminoglycans[J].Biachem Biophys Res Commun,2005,333:976-983.
[4]Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease [J]. Matrix Biol.2011,30:83-92.
[5]Urbich C, Reissner A, Chavakis E, Dernbach E, Haendeler J, Fleming I, Zeiher AM, Kaszkin M, Dimmeler S. Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin [J].FASEB J,2002,16:706-718.
[6]Lu N, Ling Y, Gao Y, Chen Y, Mu R, Qi Q, Liu W, Zhang H, Gu H, Wang S, Yang Y, Guo Q. Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells [J]. Exp Biol Med (maywood),2008,233:1013-1020.
[7]Richter AG, McKeown S, Rathinam S, Harper L, Rajesh P, McAuley DF, Heljasvaara R, Thickett DR. Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis[J].Thorax,2009,64:156-161.
[8]Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta3 and alpha5 betal integrins [J]. Proc Nat1 Acad Sci USA,2003,100:4766-4771.
[9]Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, Ramchandran R, Pestell R, Sukhatme VP. Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1 [J].Chem,2002,277:16464-16469.
[10]Nguyen TM, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels[J]. J Cell Mol Med,2009,13:3687-3698.
[11]Yuan S, Fu Y, Wang X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis[J]. FASEB J,2008,22:2809-2820.
[12]MacDonald NJ, Shivers WY, Narum DL, Plum SM, Wingard JN, Fuhrmann SR, Liang H, Holland-Linn J, Chen DH, Sim BK. Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin[J]. J Biol Chem,2001,276:25190-25196.
[13]Dixelius J,Larsson H,Sasaki T, Holmqvist K, Lu L, Engstrom A, Timpl R, Welsh M, Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis [J].Blood,2000,95:3403-3411.
[14]Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, Luo Y. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin[J]. Blood,2007,110:2899-2906.
[15]Zia A. Khan, Juan M. Paruchuri S, Boscolo E, Mulliken JB, Bischoff J. Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin[J].Blood,2006,108:915-921.
[16]Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, Koster J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization[J]. Eur Heart J,2007, 28:2018-2027.
[17]Watorek E, Paprocka M, Dus D, Kopec W, Klinger M. Endostatin and vascular endothelial growth factor:potential regulators of endothelial progenitor cell number in chronic kidney disease [J]. Pol Arch Med Wewn,2011,121:296-301.
[18]Capillo M, Mancuso P, Gobbi A, Monestiroli S, Pruneri G, Dell'Agnola C, Martinelli G, Shultz L, Bertolini F. Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors[J].Clin Cancer Res. 2003,9:377-382.
[19]Schuch G, Heymach JV, Nomi M, Machluf M, Force J, Atala A, Eder JP Jr, Folkman J, Soker S. Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells[J]. Cancer Res,2003,63:8345-8350.
[20]Schmidt A, Addicks K, Bloch W. Opposite effects of endostatin on different endothelial cells[J].Cancer Biol Ther,2004,3:1162-1166.
[21]Schmidt A, Sommer F, Reiner M, Klotz T, Engelmann U, Addicks K, Bloch W. Differential endostatin binding to bladder, prostate and kidney tumour vessels[J]. BJU Int, 2005,95:174-179.
[22]Dixelius J, Cross M, Matsumoto T, Sasaki T, Timpl R, Claesson-Welsh L. Endostatin regulates endothelial cell adhesion and cytoskeletal organization[J].Cancer Res,2002,62:1944-1947.
[23]Michaels J 5th, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration [J]. Wound Repair Regen,2005,13:506-512.
[24]Schmidt A,Wenzel D,Thorey I, Sasaki T, Hescheler J, Timpl R, Addicks K, Werner S, Fleischmann BK, Bloch W. Endostatin influences endothelial morphology via the activated ERK1/2-kinase endothelial morphology and signal transduction[J]. Microvasc Res. 2006,71:152-162.
[25]Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing [J]. J Surg Res,2000,91:26-31.
[26]Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while over expression of its endostatin domain leads to delayed healing [J]. Matrix Biol,2008,27:535-546.
[27]Bloch W,Huggel K,Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing [J].FASEB J,2000,14:2373-2386.
[28]Petersen W, Pufe T, Starke C, Fuchs T, Kopf S, Raschke M, Becker R, Tillmann B. Locally applied angiogenic factors--a new therapeutic tool for meniscal repair[J]. Ann Anat,2005,187:509-519.
[29]Mundhenke C, Thomas JP, Wilding G, Lee FT, Kelzc F, Chappell R, Neider R, Sebree LA, Friedl A. Tissue examination to monitor antiangiogenic therapy:a phase I clinical trial with endostatin [J]. Clin Cancer Res,2001,7:3366-3374.
[30]Mogili NS, Krishnaswamy VR, Jayaraman M, Rajaram R, Venkatraman A, Korrapati PS. Altered angiogenic balance in keloids:a key to therapeutic intervention[J]. Transl Res, 2012,159:182-189.
[31]王棚,薛斌,江黎珠,雷彬,宋鹏宇,丁云鹏,李晶,蒋娟.重组人血管内皮抑制素可抑制兔耳增生性瘢痕[J].中国组织工程研究与临床康复,2011,15：8689-8692.
[32]王西樵,刘英开,宋菲,徐连菊,青春,陆树良.内皮抑素局部注射对兔耳增生性瘢痕的影响[J].上海交通大学学报(医学版),2011,31：1672-1675,1701.
[33]Capla JM, Ceradini DJ, Tepper OM, Callaghan MJ, Bhatt KA, Galiano RD, Levine JP, Gurtner GC. Skin graft vascularization involves precisely regulated regression and replacement of endothelial cells through both angiogenesis and vasculogenesis [J]. Plastic Reconstr Surg,2006,117:836-844.
[2]O Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J.Endostatin:an endogenous inhibitor of angiogenesis and tumor growth [J].Cell,1997,88(2):277-285.
[3]Folkman J. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action[J]. Exp Cell Res,2006,312(5):594-607.
[4]李虎,李小静,宁金龙,孟刚,高凤山,董继英.血管生长抑制因子对兔耳增生性瘢痕的作用及意义[J].中华医学美学美容杂志,2007,13(4)：237-239.
[5]王棚,薛斌,江黎珠,雷彬,宋鹏宇,丁云鹏,李晶,蒋娟.重组人血管内皮抑制素可抑制兔耳增生性瘢痕[J].中国组织工程研究与临床康复,2011,15(46)：8689-8692.
[6]Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing [J].FASEB J,2000,14(15):2373-2376.
[7]Michaels J 5th, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration [J]. Wound Repair Regen,2005,13(5):506-512.
[8]Petersen W, Pufe T, Starke C, Fuchs T, Kopf S, Raschke M, Becker R, Tillmann B. Locally applied angiogenic factors-a new therapeutic tool for meniscal repair [J]. Ann Anat,2005,187(5-6):509-519.
[9]Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing [J]. J Surg Res,2000,91(1):26-31.
[10]Mundhenke C, Thomas JP, Wilding G, Lee FT, Kelzc F, Chappell R, Neider R, Sebree LA, Friedl A. Tissue examination to monitor antiangiogenic therapy:a phase I clinical trial with endostatin [J]. Clin Cancer Res,2001,7(11):3366-3374.
[11]Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while over expression of its endostatin domain leads to delayed healing [J]. Matrix Biol,2008,27(6):535-546.
[12]Azzi A, boscoboinik D, Hensey C. The protein kinase C family [J]. Eur J Biochem,1992, 208(3):547-557.
[13]张丹.蛋白激酶C亚型与癌肿[J].辽宁医学杂志,2009,32(5)：265-268.
[14]Parekh DB, ZiegIer W, Parker PJ. Multiple pathways control protein kinase C phosphoryIation [J]. Embo J,2000,19(4):496-503.
[15]向敏,徐永健.周期蛋白D1在香烟烟雾致人肺动脉平滑肌细胞增殖中作用及其与蛋白激酶C-α关系的研究[D].华中科技大学博士学位论文,2010,5.
[16]Zhou LY, Disatnik M, Herron GS, Mochly-Rosen D, Karasek MA. Differential activation of protein kinase C isozymes by phorbol ester and collagen in human skin microvascular endothelial cells [J]. J Invest Dermatol,1996,107(2):248-252.
[17]Wellner M, Maasch C, Kupprion C, Lindschau C, Luft FC, Haller H. The proliferative effect of vascular endothelial growth factor requires protein kinase C-alpha and protein kinase C-zeta[J].Arterioscler Thro -mb Vasc Biol,1999,19(1):178-185.
[18]Yasunari K, Kohno M, Kano H, Minami M, Yoshikawa J. Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose[J]. Hypertension,2000,35(5):1092-1098.
[19]Tang S, Morgan KG, Parker C, Ware JA. Requirement for protein kinase C theta for cell cycle progression and formation of actin stress fibers and filopodia in vascular endothelial cells [J]. J Biol Chem,1997,272(45):28704-28711.
[20]Daviet I, Herbert JM, Maffrand M. Tumor-promoting phorbol esters stimulate bovine cerebral cortex capillary endothelial cell growth in vitro [J]. Biochem Biophys Res Commun, 1989,158(2):584-589.
[21]Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct alpha v Integrins[J].Science,1995,270(5241):1500-1502.
[22]Ilan N, Mahooti S, Madri JA.Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis [J]. J Cell Sci,1998,111 (Pt 24):3621-3631.
[23]Doctrow SR, Folkman J. Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens [J]. J Cell Biol,1987,104(3): 679-687
[24]Kosaka C, Sasaguri T, Ishida A, Ogata J. Cell cycle arrest in the G2 phase induced by phorbol ester and diacylglycerol in vascular endothelial cells [J]. Am J Physiol,1996,270(lPtl) C170-C178.
[25]Gailit J, Clark RA. Wound repair in the context of extracellular matrix [J]. Curr Opin Cell Biol,1994,6(5):717-725.
[26]Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D. The alpha isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells [J]. Mol Biol Cell,2000,11(3):1077-1092.
[27]Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication [J]. J Cell Biol,2000,149(7):1503-1512.
[28]Richards TS, Dunn CA, Carter WG, Usui ML, Olerud JE, Lampe PD. Richards TS, Dunn CA, Carter WG, et al. Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368[J]. J Cell Biol,2004,167(3):555-562.
[29]Alt A, Ohba M, Li L, Gartsbein M, Belanger A, Denning MF, Kuroki T, Yuspa SH, Tennenbaum T. Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment [J]. Cancer Res,2001,61(11):4591-4598
[30]Rabinovitz I, Tsomo L, Mercurio AM. Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes [J]. Mol Cell Biol,2004,24(10):4351-4360
[31]Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Epidermal growth factor induces fibronectin expression in human dermal fibroblasts via protein kinase C delta signaling pathway[J]. J Invest Dermatol,2004,122(6):1390-1398.
[32]Zhang XF, Guo SZ, Lu KH, Li HY, Li XD, Zhang LX, Yang L. Different roles of PKC and PKA in effect of interferon-y on proliferation and collagen synthesis of fibroblasts[J]. Acta Pharmacol Sin,2004,25(10):1320-1326.
[33]Chida K, Hara T, Hirai T, Konishi C, Nakamura K, Nakao K, Aiba A, Katsuki M, Kuroki T. Disruption of protein kinase C eta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis[J]. Cancer Res,2003,63(10):2404-2408.
[34]Leask A, Shi-Wen X, Khan K, Chen Y, Holmes A, Eastwood M, Denton CP, Black CM, Abraham DJ. Loss of protein kinase C-epsilon results in impaired cutaneous wound closure and myofibroblast function [J]. Cell Sci,2008,121 (Pt20):3459-3467.
[35]张选奋,郭树忠,张琳西,刘凯IFN-y抑制兔耳皮肤伤口愈合和瘢痕增生中蛋白激酶C的活性变化[J].中华整形外科杂志,2006,22(6)：442-444.
[36]时荣,张选奋.皮肤创伤再生和瘢痕愈合中Ⅰ、Ⅲ型胶原和PKC-γ、-λ的差异表达[D].兰州大学硕士学位论文,2012,5.
[37]Li X, Hahn CN, Parsons M, Drew J, Vadas MA, Gamble JR. Role of protein kinase C zeta in thrombin-induced endothelial permeability changes:inhibition by angiopoietin-1[J]. Blood,2004,104(6):1716-1724.
[38]Cardell M, Landsend AS, Eidet J, Wieloch T, Blackstad TW, Ottersen OP. High resolution immunogold analysis reveals distinct subcellular compartmentalization of protein kinase C gamma and delta in rat Purkinje cells [J]. Neuroscience,1998,82(3):709-725.
[39]Shimohama S, Uehara-Kunugi Y, Terai K, Taniguchi T, Kimura J, Saitoh T. Expression of protein kinase C isozymes inprimary neuronal cultures of the rat cerebellum[J]. J Neurosci Res,1991,29(2):261-270.
[40]Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO. Protein kinase C isozymes and the regulation of diverse cell responses [J]. Am J Physiol Lung Cell Mol Physiol,2000,279(3):L429-438.
[41]Lo LW, Cheng JJ, Chiu JJ. Endothelial exposure to hypoxia induces Egr-1 expression involving PKCalpha-mediated Ras/Raf-1/ERK1/2 pathway[J]. J Cell Physiol, 2001,188(3):304-312.
[42]Cheng JJ, Wung BS, Chao YJ, Wang DL. Sequential activation of protein kinase C (PKC)-alpha and PKC-epsilon contributes to sustained Raf/ERK1/2 activation in endothelial cells under mechanical strain [J]. J Biol Chem,2001,276(33):31368-31375.
[43]Mandil R, Ashkenazi E, Blass M, Kronfeld I, Kazimirsky G, Rosenthal G, Umansky F, Lorenzo PS, Blumberg PM, Brodie C. Protein kinase Ca and protein kinase Cδ play opposite roles in the proliferation and apoptosisof glioma cells[J]. Cancer Res,2001,61 (11): 4612-4619.
[44]Ways DK, Kukoly CA, deVente J, Hooker JL, Bryant WO, Posekany KJ, Fletcher DJ, Cook PP, Parker PJ. MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype [J]. J Clin Invest,1995,95(4):1906-1915.
[45]Borner C, Filipuzzi I, Weinstein IB, Imber R. Failure of wild-type or a mutant form of protein kinase C-alpha to transform fibroblasts [J]. Nature,1991,353(6339):78-80.
[46]晏晓明,黄萍.PKC对人角膜基质细胞增殖的影响及对细胞周期的调控作用[A]；第七届全国角膜病及眼表疾病学术会议[C],2003.
[47]Ng T, Shima D, Squire A, Bastiaens PI, Gschmeissner S, Humphries MJ, Parker PJ. PKC alpha regulates betal integrin-dependent cell motility through association and control of integrin trafic [J]. EMBO J,1999,18(14):3909-3923.
[48]Morris DE, Wu L, Zhao LL, Bolton L, Roth SI, Ladin DA, Mustoe TA. Acute and chronic animal models for excessive dermal scarring:quantitative studies[J]. Plast Reconst Surg,1997,100(3):674-681.
[49]柳大烈,李希军,张阳,李玉霞.外源性透明质酸对创面愈合的影响[J].中国修复重建外科杂志,2002,16(4)：256-258.
[50]Pareek G, Shevchuk M, Armenakas NA, Vasjovic L, Hochberg DA, Basillote JB, Fracchia JA.The effect of finasteride on the expression of vascular endothelial growth factor and microvessel density:a possible mechanism for decreased prostatic bleeding in treated patients [J]. J Urol,2003,169(1):20-23.
[51]朱长举,陆旭,朱盛兴,赵永福,马秀现,张水军.灯盏花素对脑死亡巴马小型猪心脏结构、功能及蛋白激酶C表达的影响[J].西安交通大学学报(医学版),2007,28(1)：303-306.
[52]武元元,叶兰萍,张选奋.内皮抑素对新血管形成和皮肤创伤修复的影响.中华实验外科杂志[J].2013,30(3)：467-468.
[53]Schmidt A, Addicks K, Bloch W. Opposite effects of endostatin on different endothelial cells[J].Cancer Biol Ther,2004,3(11):1162-1166.
[54]袁中芳,魏增涛,王晓.重组内皮抑素抑制兔角膜新生血管的实验研究[J].山东大学耳鼻喉眼学报,2006,20(6)：552-554,558.
[55]王西樵,刘英开,宋菲,徐连菊,青春,陆树良.内皮抑素局部注射对兔耳增生性瘢痕的影响[J].上海交通大学学报(医学版),2011,31(12)：1672-1675,1701.
[56]张选奋,郭树忠,张琳西,刘凯TGF-β1对兔耳创面肉芽组织和瘢痕组织蛋白激酶C活性的影响[J].中国美容医学杂志,2004,13(2)：140-142.
[57]Hanauske AR, Sundell K, Lahn M. The role of protein kinase C-alpha (PKC-alpha) in cancer and its modulation by the novel PKC-alpha-specific inhibitor aprinocarsen [J].Curr Pharm Des,2004,10(16):1923-1936.
[58]Nakashima S. Protein kinase Ca (PKCa):Regulation and Biological Function [J]. J Biochem, 2002,132(5):669-675.
[59]Shimamura K, Takashiro Y, Akiyama N, Hirabayashi T, Murayama T. Expression of adhesion molecules by sphingosine 1-phosphate and histamine in endothelial cells[J]. Eur J Pharmacol,2004,486(2):141-150.
[60]万沁,童南伟,刘小菁,吴惠.高糖对血管内皮细胞蛋白激酶Ca和表达及功能的影响[J].中国糖尿病杂志,2007,,15(8)：505-506.
[61]Wang A, Nomura M, Patan S, Ware JA. Inhibition of protein kinase C alpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo [J]. Circ Res,2002,90(5):609-616.
[62]Chandrasekher G, Bazan NG, Bazan HE.Selective changes in protein kinase C (PKC) isoform expression in rabbit corneal epithelium during wound healing. Inhibition of corneal epithelial repair by PKCalpha antisense [J]. Exp Eye Res,1998,67(5):603-610.
[63]Bokhari SM, Zhou L, Karasek MA, Paturi SG, Chaudhuri V. Regulation of skin microvasculature angiogenesis, cell migration, and permeability by a specific inhibitor of PKC alpha [J]. J Invest Dermatol,2006,126(2):460-467.
[64]Lin N, Bazan HE. Protein kinase C subspecies in rabbit corneal epithelium:increased activity of alpha subspecies during wound healing [J]. Curr Eye Res,1992,11(9):899-907.
[1]周明,王远东,凌国辉, 程国华,韩国栋,邹青峰,王建,谭小军,杨嵘皓,卢家玲.重组人血管内皮抑素与化疗联合治疗肺癌的时序性研究[J].中华实验外科杂志,2011,28：1743-1745.
[2]吕纯业,邵成浩,胡先贵,张怡杰,刘瑞,金钢.转染人Endostatin基因对胰腺癌SW1990 细胞增殖、凋亡及血管内皮生长因子表达的影响[J].中华实验外科杂志,2007,24：826-828.
[3]Reis RC, Schuppan D, Barreto AC, Bork JP, Hassler G, Coelho-Sampaio T. Endostatin competes with bFGF for binding to heparin-like glycosaminoglycans[J].Biachem Biophys Res Commun,2005,333:976-983.
[4]Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease [J]. Matrix Biol.2011,30:83-92.
[5]Urbich C, Reissner A, Chavakis E, Dernbach E, Haendeler J, Fleming I, Zeiher AM, Kaszkin M, Dimmeler S. Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin [J].FASEB J,2002,16:706-718.
[6]Lu N, Ling Y, Gao Y, Chen Y, Mu R, Qi Q, Liu W, Zhang H, Gu H, Wang S, Yang Y, Guo Q. Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2/9 in MDA-MB-435 human breast cancer cells [J]. Exp Biol Med (maywood),2008,233:1013-1020.
[7]Richter AG, McKeown S, Rathinam S, Harper L, Rajesh P, McAuley DF, Heljasvaara R, Thickett DR. Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis[J].Thorax,2009,64:156-161.
[8]Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta3 and alpha5 betal integrins [J]. Proc Nat1 Acad Sci USA,2003,100:4766-4771.
[9]Hanai J, Dhanabal M, Karumanchi SA, Albanese C, Waterman M, Chan B, Ramchandran R, Pestell R, Sukhatme VP. Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1 [J].Chem,2002,277:16464-16469.
[10]Nguyen TM, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels[J]. J Cell Mol Med,2009,13:3687-3698.
[11]Yuan S, Fu Y, Wang X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis[J]. FASEB J,2008,22:2809-2820.
[12]MacDonald NJ, Shivers WY, Narum DL, Plum SM, Wingard JN, Fuhrmann SR, Liang H, Holland-Linn J, Chen DH, Sim BK. Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin[J]. J Biol Chem,2001,276:25190-25196.
[13]Dixelius J,Larsson H,Sasaki T, Holmqvist K, Lu L, Engstrom A, Timpl R, Welsh M, Claesson-Welsh L. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis [J].Blood,2000,95:3403-3411.
[14]Shi H, Huang Y, Zhou H, Song X, Yuan S, Fu Y, Luo Y. Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin[J]. Blood,2007,110:2899-2906.
[15]Zia A. Khan, Juan M. Paruchuri S, Boscolo E, Mulliken JB, Bischoff J. Endothelial progenitor cells from infantile hemangioma and umbilical cord blood display unique cellular responses to endostatin[J].Blood,2006,108:915-921.
[16]Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, Koster J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization[J]. Eur Heart J,2007, 28:2018-2027.
[17]Watorek E, Paprocka M, Dus D, Kopec W, Klinger M. Endostatin and vascular endothelial growth factor:potential regulators of endothelial progenitor cell number in chronic kidney disease [J]. Pol Arch Med Wewn,2011,121:296-301.
[18]Capillo M, Mancuso P, Gobbi A, Monestiroli S, Pruneri G, Dell'Agnola C, Martinelli G, Shultz L, Bertolini F. Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors[J].Clin Cancer Res. 2003,9:377-382.
[19]Schuch G, Heymach JV, Nomi M, Machluf M, Force J, Atala A, Eder JP Jr, Folkman J, Soker S. Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells[J]. Cancer Res,2003,63:8345-8350.
[20]Schmidt A, Addicks K, Bloch W. Opposite effects of endostatin on different endothelial cells[J].Cancer Biol Ther,2004,3:1162-1166.
[21]Schmidt A, Sommer F, Reiner M, Klotz T, Engelmann U, Addicks K, Bloch W. Differential endostatin binding to bladder, prostate and kidney tumour vessels[J]. BJU Int, 2005,95:174-179.
[22]Dixelius J, Cross M, Matsumoto T, Sasaki T, Timpl R, Claesson-Welsh L. Endostatin regulates endothelial cell adhesion and cytoskeletal organization[J].Cancer Res,2002,62:1944-1947.
[23]Michaels J 5th, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration [J]. Wound Repair Regen,2005,13:506-512.
[24]Schmidt A,Wenzel D,Thorey I, Sasaki T, Hescheler J, Timpl R, Addicks K, Werner S, Fleischmann BK, Bloch W. Endostatin influences endothelial morphology via the activated ERK1/2-kinase endothelial morphology and signal transduction[J]. Microvasc Res. 2006,71:152-162.
[25]Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing [J]. J Surg Res,2000,91:26-31.
[26]Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while over expression of its endostatin domain leads to delayed healing [J]. Matrix Biol,2008,27:535-546.
[27]Bloch W,Huggel K,Sasaki T, Grose R, Bugnon P, Addicks K, Timpl R, Werner S. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing [J].FASEB J,2000,14:2373-2386.
[28]Petersen W, Pufe T, Starke C, Fuchs T, Kopf S, Raschke M, Becker R, Tillmann B. Locally applied angiogenic factors--a new therapeutic tool for meniscal repair[J]. Ann Anat,2005,187:509-519.
[29]Mundhenke C, Thomas JP, Wilding G, Lee FT, Kelzc F, Chappell R, Neider R, Sebree LA, Friedl A. Tissue examination to monitor antiangiogenic therapy:a phase I clinical trial with endostatin [J]. Clin Cancer Res,2001,7:3366-3374.
[30]Mogili NS, Krishnaswamy VR, Jayaraman M, Rajaram R, Venkatraman A, Korrapati PS. Altered angiogenic balance in keloids:a key to therapeutic intervention[J]. Transl Res, 2012,159:182-189.
[31]王棚,薛斌,江黎珠,雷彬,宋鹏宇,丁云鹏,李晶,蒋娟.重组人血管内皮抑制素可抑制兔耳增生性瘢痕[J].中国组织工程研究与临床康复,2011,15：8689-8692.
[32]王西樵,刘英开,宋菲,徐连菊,青春,陆树良.内皮抑素局部注射对兔耳增生性瘢痕的影响[J].上海交通大学学报(医学版),2011,31：1672-1675,1701.
[33]Capla JM, Ceradini DJ, Tepper OM, Callaghan MJ, Bhatt KA, Galiano RD, Levine JP, Gurtner GC. Skin graft vascularization involves precisely regulated regression and replacement of endothelial cells through both angiogenesis and vasculogenesis [J]. Plastic Reconstr Surg,2006,117:836-844.