血浆内毒素在牙周炎患者罹患冠心病中的作用及机制研究
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摘要
目的：通过分析牙周炎患者血浆内毒素与冠心病及其危险因素的相关性及牙周炎主要致病菌牙龈卟啉单胞菌(P.g)脂多糖(LPS)对人脐静脉内皮细胞(HUVEC)细胞间连接蛋白VE-cadherin表达及细胞增殖和调亡的影响,探讨血浆牙周炎致病菌内毒素在牙周炎患者罹患冠心病中的作用及相关机制。
方法：1.临床研究采用病例对照研究设计,于2012年5月-7月在天津医科大学第二医院干部保健科进行体检的1089人中,选取牙周炎患者201人,并根据是否存在冠心病将其分为病例组(牙周炎合并冠心病)和对照组(牙周炎不合并冠心病),同时纳入43例健康查体对象设为空白组。通过鲎试剂动态浊度法与ELISA法分别测定血浆内毒素及同型半胱氨酸含量,并根据血浆内毒素四分位数将病例组人群进一步分成Q1组(>0%且≤25%)、Q2组(>25%且≤50%)、Q3组(>50%且≤75%)和Q4组(>75%且≤100%)。同时,对全部纳入对象中的男性和老年(年龄≥65岁)亚组人群分别进行了进一步相关研究。
2.实验研究：在体外将P.g菌LPS与HUVEC共培养,根据P.g菌LPS浓度分为空白对照组、10pg/mL组、50pg/mL组、100pg/mL组及1ng/mL组。分别培养2h、6h、12h及24h后,采用Western blot和RT-PCR分别检测VE-cadherin蛋白及mRNA表达情况。培养28h后采用MTT法及流式细胞仪分别测定细胞增殖活力及凋亡情况,并通过Western blot检测caspase-3激活情况。
结果：1.在全部入选研究对象中,3组人群的年龄、内毒素、收缩压(SBP)、总胆红素(STB)、同型半胱氨酸(Hcy)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、极低密度脂蛋白胆固醇(VLDL-C)、高密度脂蛋白胆固醇(HDL-C)差别均有统计学意义(P<0.01)。在病例组人群中,舒张压(DBP)、LDL-C及STB在血浆内毒素水平四分位组间的差异均有统计学意义(P<0.05),其中LDL-C随内毒素水平升高呈逐渐增高的趋势；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.438、0.457,P均为0.000),校正年龄因素影响后,它们之间仍然存在正相关(r分别为0.349、0.423,P分别为0.003、0.000)。血浆HCY及内毒素水平增加、年龄增长和舒张压升高可能是牙周炎患者罹患冠心病的促进因素,而女性性别优势可能是其抑制因素。
2.在男性亚组中,3组人群的年龄、内毒素、SBP、DBP、STB、Hey、TC、LDL-C、VLDL-C、HDL-C差别均有统计学意义(P<0.05)。在男性病例组人群中,不同血浆内毒索水平四分位组间STB的差异有统计学意义(P<0.01)；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.427、0.452,p均小于0.000),校正年龄因素影响后,它们之间J仍然存在正相关(r分别为0.361、0.454,P分别为0.006、0.000)。血浆Hcy及内毒素水平增加和年龄增长可能是促进男性牙周炎患者罹患冠心病的影响因素,而血浆Fbg水平增加可能是其抑制因素。
3.在老年亚组中,3组人群的年龄、内毒素、SBP、STB、Hcy、TC、LDL-C、 HDL-C差别均有统计学意义(P<0.05)。在老年病例组人群中,STB和DBP在血浆毒素水平四分位组间的差异均有统计学意义(P<0.05)；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.418、0.443,P均小于0.000),校正年龄因素影响后它们之间仍然存在正相关(r分别为0.320、0.399,P分别为0.008、0.001)。老年牙周炎患者罹患冠心病的易患因素可能是血.浆Hcy及内毒素水平增加,而其抑制因素可能是女性性别优势。
4.浓度为1ng/mL时,P.g菌LPS能以时间依赖方式下调HUVEC细胞VE-cadherin蛋白及mRNA表达；100pg/mL浓度的P.g菌LPS仅在处理24h后才表现出上述下调作用；而10pg/mL和50pg/mL浓度的P.g菌LPS对HUVEC细胞VE-cadherin蛋白及mRNA表达无明显影响。
5. HUVEC细胞增殖活力在10pg/mL组与空白对照组之间的差异没有统计学意义(P>0.05),细胞凋亡和caspase-3激活程度在这两组间也没有明显差异；50pg/mL组、100pg/mL组和1ng/mL组HUVEC细胞增殖活力明显低于空白对照组及10pg/mL组(P<0.01),并且随着P.g菌LPS浓度增加,HUVEC细胞增殖活力逐渐减低,而HUVEC细胞发生凋亡及caspase-3激活程度却逐渐增加。
结论：1.血浆中牙周炎致病菌内毒素水平增加可能是促使牙周炎患者罹患冠心病的影响因素,并且牙周炎致病菌内毒素可能是通过与血.浆TC、LDL-C和Hcy及年龄增长等因素协同作用共同促进冠心病的发生与发展。
2.牙周炎主要致病菌P.g菌脂多糖可能是通过抑制HUVEC细胞增殖和诱导HUVEC细胞凋亡的机制,直接引起血管内皮损伤,从而促进动脉粥样硬化病变的发生发展。
3.P.g菌LPS可能不是通过直接影响HUVEC细胞VE-cadherin表达的途径增加内皮细胞间通透性,以利于动脉粥样硬化病变的形成。
4.P.g菌LPS可能是通过激活caspase-3途径诱导HUVEC细胞产生凋亡的。
Objective:Through analysis the correlation between plasma endotoxin and coronary heart disease as well as its risk factors in patients with periodontitis and the effect of porphyromonas gingivalis-lipopolysaccharide (P.g-LPS) on VE-cadherin expression, cell proliferation and apoptosis in human umbilical vein endothelial cels (HUVEC), to study the role and mechanism of plasma periodontal pathogens endotoxin in periodontitis patients suffering from coronary heart disease (CHD).
Method:1. Clinical studies using a case-control study design, two hundred and one patients with periodontitis were choosed frome1089physical examination population, which were examined at the Second Hospital of Tianjin Medical University cadres Health Division in May-July2012. All of the201patients were divided into the case group (with both of periodontitis and CHD) and the control group (with periodontitis, but not CHD). Fourty and three healthy people were included as blank group. The plasma endotoxin and homocysteine were analyised through limulus Amebocyte lysate assay and ELISA assay, respectively. According to quartiles of plasma endotoxin, the case group people were divided into Ql group (>0%and≤25%), Q2group(>25%and≤50%), Q3group(>50%and≤75%) and Q4group(>75%and≤100%). At the same time, further study were done in male and elderly (≥65years) subgroup.
2. Experimental trails:In vitro, P.g-LPS and HUVEC were co-cultured. According to the concentration of P.g-LPS, the cells were divided into blank control group,10pg/mL group,50pg/mL group,100pg/mL group and1ng/mL group. After incubated for2h,6h,12h and24h, VE-cadherin protein and mRNA expression were detected by Western blot and RT-PCR, respectively. After incubated for28h, the cell proliferation activity and apoptosis were detected by MTT assay and flow cytometry assay, and the activation of caspase-3was detected by Western blot, aslo.
Results:1. In All of the study objectes, the difference of the age, endotoxin, systolic blood pressure (SBP), total bilirubin (STB), homocysteine (Hcy), total cholesterol (TC), lowdensity lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C) and high-density lipoprotein cholesterol (HDL-C) during the3groups were statistically significant (P<0.01). During the case group population, the difference of diastolic blood pressure (DBP), LDL-C and STB were statistically significant (F<0.05) in plasma endotoxin levels quartile groups and with increasing of endotoxin levels, LDL-C levels showed a trend of gradually increase, and we discovered positive correlation between plasma endotoxin and TC and LDL-C (R=0.438,0.457; P=0.000). After adjusting for age factors, they also ran a positive correlation (R=0.349,0.423; P=0.003,0.000). Increasing of plasma Hcy, endotoxin and DBP, and aging may be the promote factors of periodontitis patients suffering from CHD, but female gender advantage was a protective factor.
2. In male subgroup, the difference of the age, endotoxin, SBP, DBP, STB, Hcy, TC, LDL-C, VLDL-C and HDL-C during the3groups were statistically significant (P<0.05). In the case group of male subgroup, the difference of STB were statistically significant (P<0.05) in plasma endotoxin levels quartile groups, and we discovered positive correlation between plasma endotoxin and TC and LDL-C (R=0.427,0.452; F=0.000,0.000). After adjusting for age factors, they also ran a positive correlation (R=0.361,0.454; P=0.006,0.000). Increasing plasma Hey and endotoxin, and aging may promote male periodontitis patients suffering from CHD, but increasing plasma fibrinogen may be a protective factor.
3. In elderly subgroup, the difference of the age, endotoxin, SBP, STB, Hcy, TC, LDL-C and HDL-C during the3groups were statistically significant (P<0.05). In the case group of elderly subgroup, the difference of STB and DBP were statistically significant (P<0.05) in plasma endotoxin levels quartile groups, and positive correlation ship was discovered between plasma endotoxin and TC and LDL-C (R=0.418,0.443; P<0.000). After adjusting for age factors, they also ran a positive correlation (R=0.320,0.399;P=0.008,0.001). Elderly periodontitis patients with increasing plasma Hey and endotoxin may be likely to suffer from CHD, but the protective factor may be with female gender advantage.
4. P.g-LPS with concentration of1ng/mL can downregulate VE-cadherin protein and mRNA expression in the HUVEC cells with a time-dependent manner. P.g-LPS with100pg/mL showed the downward effect only after deal with24hours. However, P.g-LPS with10pg/mL and50pg/mL had no significant effect on VE-cadherin protein and mRNA expression.
5. The difference of HUVEC cell proliferation activity between10pg/mL group and blank control group was not statistically significant (P>0.05), and the degree of apoptosis and caspase-3activation in these two groups did not differ significantly. However HUVEC cell proliferation activity was significantly lower in50pg/mL group,100pg/mL group and1ng/mL group than in blank control group and10pg/mL group (P<0.01), and with concentrations increasing of P.g-LPS, the cell proliferation activity gradually decreased, but the degree of apoptosis and caspase-3activation was gradually increased.
Conclusion:1. Increased plasma periodontal pathogens endotoxin was a promote factor of periodontitis patients suffering from CHD, and it may be promote the development of CHD by joint with TC, LDL-C, Hcy and aging.
2. The LPS of periodontitis main pathogens P.g may be through inhibition of HUVEC cell proliferation and induce its apoptosis directly cause vascular endothelial injury, and promote the development of atherosclerotic lesions.
3. P.g-LPS may not increase the permeability of endothelial cells through directly affect the HUVEC cells VE-cadherin expression pathway, in order to facilitate the atherosclerosis lesion formation.
4. P.g-LPS may be induce apoptosis of HUVEC cells through activate caspase-3.
方法：1.临床研究采用病例对照研究设计,于2012年5月-7月在天津医科大学第二医院干部保健科进行体检的1089人中,选取牙周炎患者201人,并根据是否存在冠心病将其分为病例组(牙周炎合并冠心病)和对照组(牙周炎不合并冠心病),同时纳入43例健康查体对象设为空白组。通过鲎试剂动态浊度法与ELISA法分别测定血浆内毒素及同型半胱氨酸含量,并根据血浆内毒素四分位数将病例组人群进一步分成Q1组(>0%且≤25%)、Q2组(>25%且≤50%)、Q3组(>50%且≤75%)和Q4组(>75%且≤100%)。同时,对全部纳入对象中的男性和老年(年龄≥65岁)亚组人群分别进行了进一步相关研究。
2.实验研究：在体外将P.g菌LPS与HUVEC共培养,根据P.g菌LPS浓度分为空白对照组、10pg/mL组、50pg/mL组、100pg/mL组及1ng/mL组。分别培养2h、6h、12h及24h后,采用Western blot和RT-PCR分别检测VE-cadherin蛋白及mRNA表达情况。培养28h后采用MTT法及流式细胞仪分别测定细胞增殖活力及凋亡情况,并通过Western blot检测caspase-3激活情况。
结果：1.在全部入选研究对象中,3组人群的年龄、内毒素、收缩压(SBP)、总胆红素(STB)、同型半胱氨酸(Hcy)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、极低密度脂蛋白胆固醇(VLDL-C)、高密度脂蛋白胆固醇(HDL-C)差别均有统计学意义(P<0.01)。在病例组人群中,舒张压(DBP)、LDL-C及STB在血浆内毒素水平四分位组间的差异均有统计学意义(P<0.05),其中LDL-C随内毒素水平升高呈逐渐增高的趋势；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.438、0.457,P均为0.000),校正年龄因素影响后,它们之间仍然存在正相关(r分别为0.349、0.423,P分别为0.003、0.000)。血浆HCY及内毒素水平增加、年龄增长和舒张压升高可能是牙周炎患者罹患冠心病的促进因素,而女性性别优势可能是其抑制因素。
2.在男性亚组中,3组人群的年龄、内毒素、SBP、DBP、STB、Hey、TC、LDL-C、VLDL-C、HDL-C差别均有统计学意义(P<0.05)。在男性病例组人群中,不同血浆内毒索水平四分位组间STB的差异有统计学意义(P<0.01)；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.427、0.452,p均小于0.000),校正年龄因素影响后,它们之间J仍然存在正相关(r分别为0.361、0.454,P分别为0.006、0.000)。血浆Hcy及内毒素水平增加和年龄增长可能是促进男性牙周炎患者罹患冠心病的影响因素,而血浆Fbg水平增加可能是其抑制因素。
3.在老年亚组中,3组人群的年龄、内毒素、SBP、STB、Hcy、TC、LDL-C、 HDL-C差别均有统计学意义(P<0.05)。在老年病例组人群中,STB和DBP在血浆毒素水平四分位组间的差异均有统计学意义(P<0.05)；血浆内毒素与TC和LDL-C之间存在正相关(r分别为0.418、0.443,P均小于0.000),校正年龄因素影响后它们之间仍然存在正相关(r分别为0.320、0.399,P分别为0.008、0.001)。老年牙周炎患者罹患冠心病的易患因素可能是血.浆Hcy及内毒素水平增加,而其抑制因素可能是女性性别优势。
4.浓度为1ng/mL时,P.g菌LPS能以时间依赖方式下调HUVEC细胞VE-cadherin蛋白及mRNA表达；100pg/mL浓度的P.g菌LPS仅在处理24h后才表现出上述下调作用；而10pg/mL和50pg/mL浓度的P.g菌LPS对HUVEC细胞VE-cadherin蛋白及mRNA表达无明显影响。
5. HUVEC细胞增殖活力在10pg/mL组与空白对照组之间的差异没有统计学意义(P>0.05),细胞凋亡和caspase-3激活程度在这两组间也没有明显差异；50pg/mL组、100pg/mL组和1ng/mL组HUVEC细胞增殖活力明显低于空白对照组及10pg/mL组(P<0.01),并且随着P.g菌LPS浓度增加,HUVEC细胞增殖活力逐渐减低,而HUVEC细胞发生凋亡及caspase-3激活程度却逐渐增加。
结论：1.血浆中牙周炎致病菌内毒素水平增加可能是促使牙周炎患者罹患冠心病的影响因素,并且牙周炎致病菌内毒素可能是通过与血.浆TC、LDL-C和Hcy及年龄增长等因素协同作用共同促进冠心病的发生与发展。
2.牙周炎主要致病菌P.g菌脂多糖可能是通过抑制HUVEC细胞增殖和诱导HUVEC细胞凋亡的机制,直接引起血管内皮损伤,从而促进动脉粥样硬化病变的发生发展。
3.P.g菌LPS可能不是通过直接影响HUVEC细胞VE-cadherin表达的途径增加内皮细胞间通透性,以利于动脉粥样硬化病变的形成。
4.P.g菌LPS可能是通过激活caspase-3途径诱导HUVEC细胞产生凋亡的。
Objective:Through analysis the correlation between plasma endotoxin and coronary heart disease as well as its risk factors in patients with periodontitis and the effect of porphyromonas gingivalis-lipopolysaccharide (P.g-LPS) on VE-cadherin expression, cell proliferation and apoptosis in human umbilical vein endothelial cels (HUVEC), to study the role and mechanism of plasma periodontal pathogens endotoxin in periodontitis patients suffering from coronary heart disease (CHD).
Method:1. Clinical studies using a case-control study design, two hundred and one patients with periodontitis were choosed frome1089physical examination population, which were examined at the Second Hospital of Tianjin Medical University cadres Health Division in May-July2012. All of the201patients were divided into the case group (with both of periodontitis and CHD) and the control group (with periodontitis, but not CHD). Fourty and three healthy people were included as blank group. The plasma endotoxin and homocysteine were analyised through limulus Amebocyte lysate assay and ELISA assay, respectively. According to quartiles of plasma endotoxin, the case group people were divided into Ql group (>0%and≤25%), Q2group(>25%and≤50%), Q3group(>50%and≤75%) and Q4group(>75%and≤100%). At the same time, further study were done in male and elderly (≥65years) subgroup.
2. Experimental trails:In vitro, P.g-LPS and HUVEC were co-cultured. According to the concentration of P.g-LPS, the cells were divided into blank control group,10pg/mL group,50pg/mL group,100pg/mL group and1ng/mL group. After incubated for2h,6h,12h and24h, VE-cadherin protein and mRNA expression were detected by Western blot and RT-PCR, respectively. After incubated for28h, the cell proliferation activity and apoptosis were detected by MTT assay and flow cytometry assay, and the activation of caspase-3was detected by Western blot, aslo.
Results:1. In All of the study objectes, the difference of the age, endotoxin, systolic blood pressure (SBP), total bilirubin (STB), homocysteine (Hcy), total cholesterol (TC), lowdensity lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C) and high-density lipoprotein cholesterol (HDL-C) during the3groups were statistically significant (P<0.01). During the case group population, the difference of diastolic blood pressure (DBP), LDL-C and STB were statistically significant (F<0.05) in plasma endotoxin levels quartile groups and with increasing of endotoxin levels, LDL-C levels showed a trend of gradually increase, and we discovered positive correlation between plasma endotoxin and TC and LDL-C (R=0.438,0.457; P=0.000). After adjusting for age factors, they also ran a positive correlation (R=0.349,0.423; P=0.003,0.000). Increasing of plasma Hcy, endotoxin and DBP, and aging may be the promote factors of periodontitis patients suffering from CHD, but female gender advantage was a protective factor.
2. In male subgroup, the difference of the age, endotoxin, SBP, DBP, STB, Hcy, TC, LDL-C, VLDL-C and HDL-C during the3groups were statistically significant (P<0.05). In the case group of male subgroup, the difference of STB were statistically significant (P<0.05) in plasma endotoxin levels quartile groups, and we discovered positive correlation between plasma endotoxin and TC and LDL-C (R=0.427,0.452; F=0.000,0.000). After adjusting for age factors, they also ran a positive correlation (R=0.361,0.454; P=0.006,0.000). Increasing plasma Hey and endotoxin, and aging may promote male periodontitis patients suffering from CHD, but increasing plasma fibrinogen may be a protective factor.
3. In elderly subgroup, the difference of the age, endotoxin, SBP, STB, Hcy, TC, LDL-C and HDL-C during the3groups were statistically significant (P<0.05). In the case group of elderly subgroup, the difference of STB and DBP were statistically significant (P<0.05) in plasma endotoxin levels quartile groups, and positive correlation ship was discovered between plasma endotoxin and TC and LDL-C (R=0.418,0.443; P<0.000). After adjusting for age factors, they also ran a positive correlation (R=0.320,0.399;P=0.008,0.001). Elderly periodontitis patients with increasing plasma Hey and endotoxin may be likely to suffer from CHD, but the protective factor may be with female gender advantage.
4. P.g-LPS with concentration of1ng/mL can downregulate VE-cadherin protein and mRNA expression in the HUVEC cells with a time-dependent manner. P.g-LPS with100pg/mL showed the downward effect only after deal with24hours. However, P.g-LPS with10pg/mL and50pg/mL had no significant effect on VE-cadherin protein and mRNA expression.
5. The difference of HUVEC cell proliferation activity between10pg/mL group and blank control group was not statistically significant (P>0.05), and the degree of apoptosis and caspase-3activation in these two groups did not differ significantly. However HUVEC cell proliferation activity was significantly lower in50pg/mL group,100pg/mL group and1ng/mL group than in blank control group and10pg/mL group (P<0.01), and with concentrations increasing of P.g-LPS, the cell proliferation activity gradually decreased, but the degree of apoptosis and caspase-3activation was gradually increased.
Conclusion:1. Increased plasma periodontal pathogens endotoxin was a promote factor of periodontitis patients suffering from CHD, and it may be promote the development of CHD by joint with TC, LDL-C, Hcy and aging.
2. The LPS of periodontitis main pathogens P.g may be through inhibition of HUVEC cell proliferation and induce its apoptosis directly cause vascular endothelial injury, and promote the development of atherosclerotic lesions.
3. P.g-LPS may not increase the permeability of endothelial cells through directly affect the HUVEC cells VE-cadherin expression pathway, in order to facilitate the atherosclerosis lesion formation.
4. P.g-LPS may be induce apoptosis of HUVEC cells through activate caspase-3.
引文
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