九里香叶总黄酮及其单体对糖尿病心肌病的保护作用及机制
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摘要
糖尿病心肌病是糖尿病的主要并发症之一，随着糖尿病患者的逐年增多，糖尿病心肌病的发病率也迅速上升。糖尿病心肌病的主要因素是由心肌能量代谢异常，包括糖和乳酸盐代谢减少，脂肪代谢增加导致游离脂肪酸堆积以及由此导致的体内稳态失衡。在此基础上出现氧化应激，最终导致细胞凋亡、炎症反应增加、内皮功能紊乱以及血液高凝和心肌纤维化等病理生理改变，同时出现线粒体、细胞微循环的损伤，间质纤维化，心肌的功能和结构均发生改变。九里香叶总黄酮（TFMP）是从九里香叶中提取的黄酮类化合物，纯度达到92%以上。研究表明，TFMP是由一系列极性很小的甲氧基黄酮类化合物组成，其中两种含量最高的单体成分是JA（40.96%）和JB（31.05%）。
本研究在整体水平，观察TFMP对高糖高脂饮食伴小剂量链脲佐菌素诱导大鼠糖尿病心肌病的影响，探讨TFMP对糖尿病心肌病的保护作用；在细胞水平，观察TFMP、JA及JB对高糖诱导H9c2心肌细胞凋亡的影响，探讨TFMP、JA及JB对高糖诱导H9c2心肌细胞凋亡的保护作用及机制。主要研究内容如下：
1.整体水平研究利用高糖高脂饮食伴小剂量链脲佐菌素（30mg/kg）建立大鼠2型糖尿病模型，给予TFMP12周，检测大鼠血糖、血脂、自由基氧化损伤、炎性因子和心肌病理等改变。结果表明，灌胃给予TFMP35、70mg/kg12周，可明显改善2型糖尿病大鼠的心肌结构损伤，纠正血糖、血脂代谢紊乱，抑制心肌纤维化主要炎性因子（IL-6，TGF-β1，CTGF）的增高，对抗自由基的氧化损伤。整体实验结果说明，TFMP能明显改善2型糖尿病大鼠的心肌损伤。
2.细胞水平研究通过不同浓度葡萄糖（20、30、50、100mmol/L）刺激H9c2心肌细胞，观察不同浓度葡萄糖对H9c2心肌细胞的存活率、乳酸脱氢酶（LDH）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）、caspase-3，NADPH氧化酶p47phox蛋白的影响。结果显示，高浓度葡萄糖（30、50、100mmol/L）可明显诱导H9c2心肌细胞氧化损伤及凋亡。
3.作用机制研究通过高糖（30mmol/L）刺激诱导H9c2心肌细胞氧化损伤及凋亡，并用TFMP、JA及JB干预，检测H9c2心肌细胞氧化应激及凋亡信号转导通路等蛋白的表达。结果显示：TFMP、JA及JB能改善高糖诱导H9c2心肌细胞的氧化应激损伤，减少caspase-3的活性及蛋白表达，降低p38MAPK、JNK、NF-κB及NADPH氧化酶p47phox的蛋白表达，并可提高Bcl-2/Bax比值、抑制细胞凋亡，其保护糖尿病心肌病的作用机制可能与p38MAPK、JNK、NF-κB，caspase-3信号转导通路的激活有关。
综上所述，TFMP对糖尿病心肌病具有保护作用，其机制可能与抑制氧化应激损伤诱导的心肌细胞凋亡有关。研究结果表明，单体黄酮JA、JB同样通过抑制氧化应激损伤诱导心肌细胞凋亡的机制保护糖尿病心肌损伤，从而确证了单体黄酮JA及JB是TFMP保护糖尿病心肌病的主要有效成份。
Cardiovascular complications, including diabetic cardiomyopathy (DCM), havebecome one of the leading causes of the rising morbidity and mortality in both type1and type2diabetes. In addition, DCM, as an independent diabetic cardiaccomplication, is characterized by the myocardial dysfunction in the absence ofhypertension, coronary artery or valvular heart disease which increases the risk ofheart failure. The mainly clinical feature of DCM is left ventricular hypertrophy anddiastolic dysfunction and will occur systolic dysfunction with the progression.
TFMP was extract from the leaves of Murraya paniculata (L.) Jack (TFMP). Thecontent of flavonoid was more than92%. The study showed that TFMP wascomposed of a series of small polar methoxy flavonoids, and proved that the highestcontent of TFMP was JA (40.96%) and JB (31.05%). Our previous study showed thatTFMP had hypoglycemic and protective effect of diabetic nephropathy. However, thestudy about the effect of TFMP、JA and JB on the progression of DCM has not beenreported.
In the thesis, we have used high fat diet and single low does STZ to inducediabetes to evaluate the protective effect of TFMP on diabetic cardiomypathy, and wehave established the model of oxidative injury and apoptosis in H9c2cells by highconcentration glucose to study the effects of TFMP、JA and JB on H9c2cellsoxidative injury and apoptosis.
Flavonoids is one of the major compounds in the leaves of Murraya paniculata.Our previous study showed that TFMP had hypoglycemic effects without harmfulside effects. Therefore, we hypothesized that TFMP may have beneficial influence onthe progression of DCM. In the present study, the effects of TFMP on DCM in highfat diet and STZ-induced diabetic rats were evaluated.
1. The protective effects of TFMP on type2diabetic rats
(1) Experimental method
The type2diabetic rats, induced by high fat diet and low dose STZ, were used toevaluate the effects of TFMP70、35mg/kg. The changes of TC, TG, HDL-c, LDL-cand IL-6in the serum of rats; the activity of SOD, GSH-Px and the content of MDAin myocardial tissue of rats; the expression of TGF-β1and CTGF in myocardial tissuewere detected. The myocardial histopathology and ultrastructure changes wereobserved.
(2) Experimental results
①Compared with the Normal group, the TC, TG, LDL-c level was increasedsignificantly and the level of HDL-c was decreased significantly in the Model group;compared with the Model group, the TC, TG, LDL-c level was decreased significantlyand the level of HDL-c was increased significantly in the TFMP70、35mg/kg group(P<0.05or P<0.01);②Diabetic rats showed a significant reduction of both SOD andGSH-Px activities while increased the level of MDA in the myocardial tissuecompared with normal rats; the avtivities of SOD, GSH-Px were elevated and thecontent of MDA was reduced significantly in the myocardial tissue of TFMP70、35mg/kg group (P<0.05or P<0.01);③The body weight was decreased and theHW/BW was increased significantly in Model group compared with Normal group;compared with Model group, the body weight was increased and the HW/BW wasdecreased significantly in the TFMP70、35mg/kg group(P<0.05or P<0.01);④In theModel group rats, the level of IL-6and the myocardial tissue staining for TGF-β1and CTGF was significantly higher than that in Normal group; However, comparedwith Model group, the level of IL-6and immunohistochemical staining for TGF-β1and CTGF in myocardial tissue was markedly less in TFMP70、35mg/kg group.⑤The lesion of heart in the TFMP70、35mg/kg were significantly improved comparedwith Model group.
2. The effects of different concentration of glucose on H9c2cells.
(1) Experimental method
To investigate the apoptosis-related signaling pathyways that are avtivated inH9c2cells treated with (20、30、50、100mmol/L) glucose. The percentage of survival cells, LDH, SOD, GSH-Px, MDA, the activity of caspase-3，AO/EB,Hoechst33342, Annexin V-FITC/PI and the protein expression of caspase-3andp47phox in H9c2cells were observed.
(2) Experimental results
①MTT assay was performed to evaluate whether high concentrations of glucoseinhibit the growth of H9c2cells. We found that high concentration of glucose (30、50、100mmol/L) had cytotoxic effect on H9c2cells;②Compared with Normal H9c2cells, the activities of SOD, GSH-Px was decreased significantly, the content of MDAwas increased significantly in high concentration of glucose (30、50、100mmol/L)induced H9c2cells (P<0.05or P<0.01);③High concentration of glucose (20、30、50、100mmol/L) could increased the activities of caspase-3in H9c2cells (P<0.05orP<0.01);④Immunofluorescence staining showed that: the high concentration ofglucose (20、30、50、100mmol/L) induced H9c2cells displayed different levels ofapoptosis;⑤Western Blot to examine the protein expression of caspase-3andp47phox in cells exposed to high concentration of glucose (20、30、50、100mmol/L).The results showed that the protein level of caspase-3and p47phox were elevatedafter high concentration of glucose treatment.
3. Effect of TFMP, JA and JB in H9c2cells exposed to high glucose and itsmechanism
(1)Experimental method
H9c2cells treated with high concentration of glucose (30mmol/L) was used asModel group. TFMP, JA and JB added into high concentration of glucose (30mmol/L)respectively were used as medicine group intervention. The H9c2cells treated withnormal glucose (5.5mmol/L) was used as Normal group. The H9c2cells of eachgroup were collected and the following measures were carried out: The activities ofSOD, GSH-Px, the content of MDA and the activity of caspase-3were assayed byavailable kits. The apoptosis was observed by staining of AO/EB and Hoechst33342.The rate of apoptosis was assayed by Annexin V-FITC kit. The expression of p47phox,p38MAPK, p-p38MAPK, JNK, p-JNK, p-NF-κB, Bcl-2, Bax, caspase-3protein weredetermined by Western Blot analysis.
(2) Experimental results
①The activities of SOD, GSH-Px were increased and the content of MDA wasdecreased significantly in TFMP, JA and JB group compared with Model group(P<0.05or P<0.01);②The activity of caspase-3was decreased in TFMP, JA and JBgroup compared with Model group (P<0.05or P<0.01);③The result of AnnexinV-FITC/PI showed that: TFMP, JA and JB can inhibited high glucose induced earlyapoptosis in H9c2cells;④TFMP, JA and JB can decreased the expression ofp47phox, caspase-3. TFMP, JA, JB can up-regulate Bcl-2protein level, and reducedBax protein level. TFMP, JA and JB can reduce the phosphorylation of p38MAPK,JNK and NF-κB. The results showed that high glucose induced oxidative stressthrough the activation of NADPH oxidase, thus activating the p38MAPK, JNK,NF-κB signaling pathway, leading to myocardial apoptosis. The mechanism of TFMP,JA and JB protective effects probably through downregulation of NADPHoxidase-ROS-p38MAPK-JNK-NF-κB signaling pathway.
In summary, TFMP has protective effect on the high fat diet and low dose STZinduced diabetic cardiomyopathy. TFMP, JA and JB can extenuate oxidative injury ofH9c2cells induced by high glucose. TFMP, JA and JB can inhibit H9c2cellsapoptosis induced by high glucose. This study preliminary clarified TFMP, JA and JBhave the protective effect of diabetic cardiomyopathy, and confirmed the monomericflavonoids JA and JB is the main active ingredient of TFMP.
本研究在整体水平，观察TFMP对高糖高脂饮食伴小剂量链脲佐菌素诱导大鼠糖尿病心肌病的影响，探讨TFMP对糖尿病心肌病的保护作用；在细胞水平，观察TFMP、JA及JB对高糖诱导H9c2心肌细胞凋亡的影响，探讨TFMP、JA及JB对高糖诱导H9c2心肌细胞凋亡的保护作用及机制。主要研究内容如下：
1.整体水平研究利用高糖高脂饮食伴小剂量链脲佐菌素（30mg/kg）建立大鼠2型糖尿病模型，给予TFMP12周，检测大鼠血糖、血脂、自由基氧化损伤、炎性因子和心肌病理等改变。结果表明，灌胃给予TFMP35、70mg/kg12周，可明显改善2型糖尿病大鼠的心肌结构损伤，纠正血糖、血脂代谢紊乱，抑制心肌纤维化主要炎性因子（IL-6，TGF-β1，CTGF）的增高，对抗自由基的氧化损伤。整体实验结果说明，TFMP能明显改善2型糖尿病大鼠的心肌损伤。
2.细胞水平研究通过不同浓度葡萄糖（20、30、50、100mmol/L）刺激H9c2心肌细胞，观察不同浓度葡萄糖对H9c2心肌细胞的存活率、乳酸脱氢酶（LDH）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）、caspase-3，NADPH氧化酶p47phox蛋白的影响。结果显示，高浓度葡萄糖（30、50、100mmol/L）可明显诱导H9c2心肌细胞氧化损伤及凋亡。
3.作用机制研究通过高糖（30mmol/L）刺激诱导H9c2心肌细胞氧化损伤及凋亡，并用TFMP、JA及JB干预，检测H9c2心肌细胞氧化应激及凋亡信号转导通路等蛋白的表达。结果显示：TFMP、JA及JB能改善高糖诱导H9c2心肌细胞的氧化应激损伤，减少caspase-3的活性及蛋白表达，降低p38MAPK、JNK、NF-κB及NADPH氧化酶p47phox的蛋白表达，并可提高Bcl-2/Bax比值、抑制细胞凋亡，其保护糖尿病心肌病的作用机制可能与p38MAPK、JNK、NF-κB，caspase-3信号转导通路的激活有关。
综上所述，TFMP对糖尿病心肌病具有保护作用，其机制可能与抑制氧化应激损伤诱导的心肌细胞凋亡有关。研究结果表明，单体黄酮JA、JB同样通过抑制氧化应激损伤诱导心肌细胞凋亡的机制保护糖尿病心肌损伤，从而确证了单体黄酮JA及JB是TFMP保护糖尿病心肌病的主要有效成份。
Cardiovascular complications, including diabetic cardiomyopathy (DCM), havebecome one of the leading causes of the rising morbidity and mortality in both type1and type2diabetes. In addition, DCM, as an independent diabetic cardiaccomplication, is characterized by the myocardial dysfunction in the absence ofhypertension, coronary artery or valvular heart disease which increases the risk ofheart failure. The mainly clinical feature of DCM is left ventricular hypertrophy anddiastolic dysfunction and will occur systolic dysfunction with the progression.
TFMP was extract from the leaves of Murraya paniculata (L.) Jack (TFMP). Thecontent of flavonoid was more than92%. The study showed that TFMP wascomposed of a series of small polar methoxy flavonoids, and proved that the highestcontent of TFMP was JA (40.96%) and JB (31.05%). Our previous study showed thatTFMP had hypoglycemic and protective effect of diabetic nephropathy. However, thestudy about the effect of TFMP、JA and JB on the progression of DCM has not beenreported.
In the thesis, we have used high fat diet and single low does STZ to inducediabetes to evaluate the protective effect of TFMP on diabetic cardiomypathy, and wehave established the model of oxidative injury and apoptosis in H9c2cells by highconcentration glucose to study the effects of TFMP、JA and JB on H9c2cellsoxidative injury and apoptosis.
Flavonoids is one of the major compounds in the leaves of Murraya paniculata.Our previous study showed that TFMP had hypoglycemic effects without harmfulside effects. Therefore, we hypothesized that TFMP may have beneficial influence onthe progression of DCM. In the present study, the effects of TFMP on DCM in highfat diet and STZ-induced diabetic rats were evaluated.
1. The protective effects of TFMP on type2diabetic rats
(1) Experimental method
The type2diabetic rats, induced by high fat diet and low dose STZ, were used toevaluate the effects of TFMP70、35mg/kg. The changes of TC, TG, HDL-c, LDL-cand IL-6in the serum of rats; the activity of SOD, GSH-Px and the content of MDAin myocardial tissue of rats; the expression of TGF-β1and CTGF in myocardial tissuewere detected. The myocardial histopathology and ultrastructure changes wereobserved.
(2) Experimental results
①Compared with the Normal group, the TC, TG, LDL-c level was increasedsignificantly and the level of HDL-c was decreased significantly in the Model group;compared with the Model group, the TC, TG, LDL-c level was decreased significantlyand the level of HDL-c was increased significantly in the TFMP70、35mg/kg group(P<0.05or P<0.01);②Diabetic rats showed a significant reduction of both SOD andGSH-Px activities while increased the level of MDA in the myocardial tissuecompared with normal rats; the avtivities of SOD, GSH-Px were elevated and thecontent of MDA was reduced significantly in the myocardial tissue of TFMP70、35mg/kg group (P<0.05or P<0.01);③The body weight was decreased and theHW/BW was increased significantly in Model group compared with Normal group;compared with Model group, the body weight was increased and the HW/BW wasdecreased significantly in the TFMP70、35mg/kg group(P<0.05or P<0.01);④In theModel group rats, the level of IL-6and the myocardial tissue staining for TGF-β1and CTGF was significantly higher than that in Normal group; However, comparedwith Model group, the level of IL-6and immunohistochemical staining for TGF-β1and CTGF in myocardial tissue was markedly less in TFMP70、35mg/kg group.⑤The lesion of heart in the TFMP70、35mg/kg were significantly improved comparedwith Model group.
2. The effects of different concentration of glucose on H9c2cells.
(1) Experimental method
To investigate the apoptosis-related signaling pathyways that are avtivated inH9c2cells treated with (20、30、50、100mmol/L) glucose. The percentage of survival cells, LDH, SOD, GSH-Px, MDA, the activity of caspase-3，AO/EB,Hoechst33342, Annexin V-FITC/PI and the protein expression of caspase-3andp47phox in H9c2cells were observed.
(2) Experimental results
①MTT assay was performed to evaluate whether high concentrations of glucoseinhibit the growth of H9c2cells. We found that high concentration of glucose (30、50、100mmol/L) had cytotoxic effect on H9c2cells;②Compared with Normal H9c2cells, the activities of SOD, GSH-Px was decreased significantly, the content of MDAwas increased significantly in high concentration of glucose (30、50、100mmol/L)induced H9c2cells (P<0.05or P<0.01);③High concentration of glucose (20、30、50、100mmol/L) could increased the activities of caspase-3in H9c2cells (P<0.05orP<0.01);④Immunofluorescence staining showed that: the high concentration ofglucose (20、30、50、100mmol/L) induced H9c2cells displayed different levels ofapoptosis;⑤Western Blot to examine the protein expression of caspase-3andp47phox in cells exposed to high concentration of glucose (20、30、50、100mmol/L).The results showed that the protein level of caspase-3and p47phox were elevatedafter high concentration of glucose treatment.
3. Effect of TFMP, JA and JB in H9c2cells exposed to high glucose and itsmechanism
(1)Experimental method
H9c2cells treated with high concentration of glucose (30mmol/L) was used asModel group. TFMP, JA and JB added into high concentration of glucose (30mmol/L)respectively were used as medicine group intervention. The H9c2cells treated withnormal glucose (5.5mmol/L) was used as Normal group. The H9c2cells of eachgroup were collected and the following measures were carried out: The activities ofSOD, GSH-Px, the content of MDA and the activity of caspase-3were assayed byavailable kits. The apoptosis was observed by staining of AO/EB and Hoechst33342.The rate of apoptosis was assayed by Annexin V-FITC kit. The expression of p47phox,p38MAPK, p-p38MAPK, JNK, p-JNK, p-NF-κB, Bcl-2, Bax, caspase-3protein weredetermined by Western Blot analysis.
(2) Experimental results
①The activities of SOD, GSH-Px were increased and the content of MDA wasdecreased significantly in TFMP, JA and JB group compared with Model group(P<0.05or P<0.01);②The activity of caspase-3was decreased in TFMP, JA and JBgroup compared with Model group (P<0.05or P<0.01);③The result of AnnexinV-FITC/PI showed that: TFMP, JA and JB can inhibited high glucose induced earlyapoptosis in H9c2cells;④TFMP, JA and JB can decreased the expression ofp47phox, caspase-3. TFMP, JA, JB can up-regulate Bcl-2protein level, and reducedBax protein level. TFMP, JA and JB can reduce the phosphorylation of p38MAPK,JNK and NF-κB. The results showed that high glucose induced oxidative stressthrough the activation of NADPH oxidase, thus activating the p38MAPK, JNK,NF-κB signaling pathway, leading to myocardial apoptosis. The mechanism of TFMP,JA and JB protective effects probably through downregulation of NADPHoxidase-ROS-p38MAPK-JNK-NF-κB signaling pathway.
In summary, TFMP has protective effect on the high fat diet and low dose STZinduced diabetic cardiomyopathy. TFMP, JA and JB can extenuate oxidative injury ofH9c2cells induced by high glucose. TFMP, JA and JB can inhibit H9c2cellsapoptosis induced by high glucose. This study preliminary clarified TFMP, JA and JBhave the protective effect of diabetic cardiomyopathy, and confirmed the monomericflavonoids JA and JB is the main active ingredient of TFMP.
引文
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