白藜芦醇抑制AGEs诱导泡沫细胞形成及血管平滑肌细胞钙化的机制研究
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摘要
研究背景
目前糖尿病(DM)发病率呈明显的逐年增高趋势,DM患者发生动脉粥样硬化(AS)及危及生命的心血管并发症较正常人显著增加。另外,糖尿病的大血管钙化包括主动脉、肾动脉、周围血管等的钙化是导致肾动脉狭窄和周围血管闭塞性疾病甚至致残的重要原因。因此,深入研究糖尿病性血管病变的发生机制,寻找重要靶点和开发新的药物具有重要意义。
持久的高血糖状态可导致DM患者体内蓄积过多的糖基化终产物(advanced glycation end products, AGEs),后者与细胞表面的AGEs受体(Receptor for AGEs, RAGE)相互作用而发挥一系列的血管病理作用,加速糖尿病血管并发症的发生发展。胆固醇酯的沉积和巨噬细胞源性的泡沫细胞形成是AS发生的早期事件和关键环节,而AGEs-RAGE对哪些脂质受体或脂质转运蛋白有调节作用,研究结果仍不一致。同时,临床资料提示,老龄、糖尿病、高血压和钙超载是动脉钙化的主要危险因素。近来发现,AGEs可促进血管平滑肌细胞(vascular smooth muscle cell, VSMC)的钙化,但其具体机制仍未完全明确。寻找阻断AGEs血管损害作用的药物并探索其机制具有重要的临床意义。
白藜芦醇(resveratro1, RESV)是一种非黄酮类多酚化合物,具有保护心血管、抗肿瘤、抗炎症、抗氧化和模拟雌激素等广泛作用,对改善胰岛素敏感性、防治糖尿病和改善内皮损伤、预防心血管重构等具有显著效果。然而,白藜芦醇对糖尿病动脉粥样斑块中巨噬细胞源性泡沫细胞的形成有何影响尚不明确,同时白藜芦醇对糖尿病条件下血管平滑肌细胞的钙化有何影响尚未见报道。
由于PPARγ在巨噬细胞脂质代谢过程中具有调节作用,而白藜芦醇可激活PPARγ,因此我们推测,白藜芦醇可能通过激活PPARγ抑制AGEs诱导的泡沫细胞形成。此外,由于VSMC钙化和骨细胞分化过程相似,而白藜芦醇可以影响骨细胞分化,我们推测白藜芦醇对AGEs作用下的VSMC钙化也有一定程度的作用。
材料方法
为了证实该推测,本研究将分为体外细胞实验和在体动物实验两部分。
第一部分以人单核细胞系THP-1源性的巨噬细胞为模型,通过检测细胞脂质摄取和转运相关蛋白的表达以及细胞内脂质含量,研究AGEs联合或不联合白藜芦醇对氧化型LDL(ox-LDL)诱导的泡沫细胞形成的影响。第二部分以原代培养的小鼠VSMC为模型,给予适当的条件诱导其向成骨细胞分化,检测相关信号通路和成骨信号分子的表达以及细胞钙含量,观察AGEs联合或不联合白藜芦醇对VSMC钙化的影响。第三部分以apoE基因敲除型小鼠为模型,给予STZ和高脂饮食联合诱导糖尿病动脉粥样硬化模型,给予含白藜芦醇的饲料进行干预,观察其对动物主动脉粥样斑块和钙化的影响。
试验步骤如下:
1.在经PMA诱导的THP-1源性巨噬细胞中加入不同浓度AGEs,以及在固定浓度AGEs作用下加入不同浓度的白藜芦醇,通过免疫印迹检测RAGE的表达变化;
2.通过免疫印迹检测白藜芦醇作用下PPARγ等分子的表达,以及加入PPARγ拮抗剂GW9662后白藜芦醇对RAGE表达的影响;
3.在AGEs和白藜芦醇作用下的巨噬细胞细胞中,检测加入或不加GW9662时CD36、SR-A、ABCA1及ABCG1等相关脂质转运基因的表达情况;
4.通过细胞内总胆固醇定量和油红O染色,检测AGEs、AGEs+白藜芦醇以及AGEs+白藜芦醇+GW9662分别对细胞内胆固醇含量和脂滴形成的影响;
5.通过定量PCR检测不同浓度白藜芦醇对VSMC钙化过程中cbfa1、sm22a和ALP的表达以及细胞钙含量的影响;
6.通过免疫印迹明确白藜芦醇对VSMC中RAGE表达及ERK1/2磷酸化的影响;
7.利用定量PCR和免疫印迹检测白藜芦醇、RAGE中和抗体、ERK1/2阻断剂分别对VSMC中cbfa1和sm22a表达的影响;
8.建立糖尿病动脉粥样硬化小鼠模型,予以白藜芦醇干预20周后测定小鼠体重、血糖、血脂等指标;
9.免疫印迹检测各组小鼠主动脉中RAGE、cbfa1、sm22a的表达情况,验证白藜芦醇对糖尿病小鼠粥样斑块形成和动脉钙化的影响;
10.通过动脉冰冻切片油红O和茜素红染色,观察各组小鼠主动脉粥样硬化和钙化情况。
结果
1. AGEs显著上调巨噬细胞RAGE的表达,而白藜芦醇可以抑制AGEs诱导的RAGE表达上调;PPARγ拮抗剂GW9662可以减弱白藜芦醇对RAGE的抑制作用;
2. AGEs可以上调SR-A的表达,降低ABCA1和ABCG1的表达,而白藜芦醇能够抑制AGEs引起的基因表达变化,但白藜芦醇的作用可被GW9662阻断;
3. AGEs显著升高巨噬细胞中总胆固醇含量,促进脂滴形成;白藜芦醇能显著抑制AGEs引起的脂质蓄积,GW9662可以阻断白藜芦醇的效应;
4.在VSMC中,白藜芦醇显著抑制AGEs诱导的cbfa1表达上调、细胞内ALP和钙含量增加,同时抑制AGEs引起的sm22a的表达降低;
5. AGEs上调VSMC中RAGE的表达,促进ERK1/2磷酸化,而白藜芦醇可以抑制AGEs的作用;
6.加入RAGE中和抗体和ERK1/2抑制剂后,同样可以抑制AGEs诱导的cbfa1表达上调和sm22a表达下降,提示RAGE和ERK1/2介导了白藜芦醇的生物学效应;
7.白藜芦醇可以降低糖尿病小鼠血浆中总胆固醇、甘油三酯及LDL-C含量,升高HDL-C水平,从而部分恢复糖尿病引起的脂质代谢紊乱;
8.白藜芦醇可以抑制糖尿病小鼠主动脉中RAGE、cbfa1的表达,上调PPARγ和sm22a的表达;同时白藜芦醇可以抑制糖尿病小鼠主动脉中粥样硬化斑块和动脉钙化斑块形成。
结论:
1.白藜芦醇通过激活PPARγ抑制RAGE表达,调控SR-A、ABCA1和ABCG1等脂质转运基因,减轻AGEs诱导的巨噬细胞内脂质蓄积,抑制泡沫细胞形成,从而抑制糖尿病apoE敲除小鼠动脉粥样硬化斑块形成。
2.白藜芦醇通过抑制RAGE-ERK1/2通路,抑制AGEs诱导的血管平滑肌细胞钙化,从而减轻糖尿病apoE敲除小鼠的主动脉钙化。
Diabetes is associated with high frequency and high severity of atherosclerosis and vascular calcification which causes most morbidity and mortality in diabetic patients. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and vascular calcification for developing therapeutic options.
Diabetic patients have increased production and reduced clearance of advanced glycation end products (AGEs). It has been well documented that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of cardiovascular disease due to oxidative stress and inflammatory responses. Furthermore, impaired macrophage lipid metabolism directly participates in the foam cell formation in diabetes. In another hand, previous studies found that AGEs increased the osteoblastic trans-differentiation of vascular smooth muscle cell (VSMC). However, these studies were inconsistent and whether the macrophage lipid accumulation and VSMC calcification was actually affected by RAGE activation was still unclear.
Resveratrol (trans-3,5,4’-trihydroxystilbene, RESV), a natural polyphenol phytoalexin, possesses various bioactivities. A recent study indicated that resveratrol inhibits foam cell formation via suppression of reactive oxygen species (ROS) generation and macrophage activation. However, it’s still unknown whether resveratrol could prevent the impairment of AGE on the lipid homeostasis in macrophages, which might partially contribute to the prevention of diabetic atherosclerosis. Furthermore, resveratrol could regulate the differentiation of osteoblast in skeletal. Considering that osteoblast differentiation and VSMC calcification share a lot of similarites, it is possible that resveratol may regulate the VSMC calcification in diabetic patients.
To test the above hypothesis, we first find that resveratrol down-regulates RAGE expression and prevents the impairment of AGEs on macrophage lipid homeostasis through PPARγactivation. Then we document that resveratrol inhibits the AGEs-induced calcification of VSMC by suppression of AGEs-RAGE-ERK1/2 pathway. Finally, the cardiovascular protective effects of resveratol were validated in diabetic apoE knockout (apoE-/-) mice in vivo.
Materials and Methods:
The present study includes in vivo and in vitro experiments. In vivo models include apoE-/- mouse and STZ-induced-diabetic apoE-/- mouse fed with or without resveratrol. In vitro experiments were carried out in THP-1 derived macrophages and in VSMC primarily cultured from the aortas of C57BL/6J mice.
1. The effects of different concentrations of AGEs on RAGE expression and cholesterol accumulation in macrophages were detected by western blot and fluorometric assay respectively.
2. The effect of resveratrol on AGEs-induced protein expression of RAGE, SR-A, ABCA1 and ABCG1 was detected by immunoblotting.
3. The effect of resveratrol on AGEs-induced acceleration of cholesterol accumulation and foam cell formation were detected by fluorometric assay and Oil-Red O staining.
4. The effects of different concentrations of resveratrol on cbfa1 and sm22a expression in VSMC were detected by Real-time PCR.
5. The ALP expression and calcium accumulation in VSMC were detected with specific assay kits.
6. The effect of resveratrol on AGEs-induced RAGE expression and ERK1/2 phosphorylation in VSMC were detected by immunoblotting.
7. The effects of resveratrol, anti-RAGE antibody and ERK1/2 inhibitor on the mRNA expression of cbfa1 and sm22a were detected by real-time PCR.
8. Diabetic atherosclerotic mice models were established by treating apoE-/- mice with STZ and high-fat diet.
9. Blood levels of glucose and lipids were detected by specific assay kits.
10. The calcificaton of VSMC and aortas were shown by alizarin red staining.
Results:
1. AGE promotes cholesterol accumulation through induction of RAGE in macrophages.
2. Resveratrol reduces AGEs-induced RAGE expression via activation of PPARγbut not PPARαnor AMPK.
3. Resveratrol reverses the effect of AGEs on the expression of proteins involved in lipid homeostasis via PPARγactivation.
4. Resveratrol prevents the AGEs-induced acceleration of cholesterol accumulation and inhibits foam cell formation via PPARγ.
5. Resveratrol inhibits AGEs-induced expression of cbfa1 and ALP, upregulates sm22a expression, and attenuates calcium accumulation in VSMC.
5. Resveratrol reduces AGEs-induced RAGE expression and ERK1/2 phosphorylation in VSMC.
6. Blocking RAGE and ERK1/2 pathway mimics the protective effect of resveratrol on AGEs-induced calcification in VSMC.
7. Dietary resveratrol lowers the levels of plasma lipids in diabetic apoE-/- mice.
8. Long-term intervention with resveratrol reduces atherosclerotic lesions and artery tunica media calcification in diabetic apoE-/- mice.
Conclusions:
1. Resveratrol inhibits AGEs-induced foam cell formation through regulating lipid transport in macrophages by suppressing RAGE expression and reduces atherosclerotic lesions in diabetic apoE-/- mice.
2. Resveratrol suppresses AGEs-induced calcification of VSMC through the inhibition of RAGE-ERK1/2 pathway and ameliorates artery tunica media calcification in diabetic apoE-/- mice.
目前糖尿病(DM)发病率呈明显的逐年增高趋势,DM患者发生动脉粥样硬化(AS)及危及生命的心血管并发症较正常人显著增加。另外,糖尿病的大血管钙化包括主动脉、肾动脉、周围血管等的钙化是导致肾动脉狭窄和周围血管闭塞性疾病甚至致残的重要原因。因此,深入研究糖尿病性血管病变的发生机制,寻找重要靶点和开发新的药物具有重要意义。
持久的高血糖状态可导致DM患者体内蓄积过多的糖基化终产物(advanced glycation end products, AGEs),后者与细胞表面的AGEs受体(Receptor for AGEs, RAGE)相互作用而发挥一系列的血管病理作用,加速糖尿病血管并发症的发生发展。胆固醇酯的沉积和巨噬细胞源性的泡沫细胞形成是AS发生的早期事件和关键环节,而AGEs-RAGE对哪些脂质受体或脂质转运蛋白有调节作用,研究结果仍不一致。同时,临床资料提示,老龄、糖尿病、高血压和钙超载是动脉钙化的主要危险因素。近来发现,AGEs可促进血管平滑肌细胞(vascular smooth muscle cell, VSMC)的钙化,但其具体机制仍未完全明确。寻找阻断AGEs血管损害作用的药物并探索其机制具有重要的临床意义。
白藜芦醇(resveratro1, RESV)是一种非黄酮类多酚化合物,具有保护心血管、抗肿瘤、抗炎症、抗氧化和模拟雌激素等广泛作用,对改善胰岛素敏感性、防治糖尿病和改善内皮损伤、预防心血管重构等具有显著效果。然而,白藜芦醇对糖尿病动脉粥样斑块中巨噬细胞源性泡沫细胞的形成有何影响尚不明确,同时白藜芦醇对糖尿病条件下血管平滑肌细胞的钙化有何影响尚未见报道。
由于PPARγ在巨噬细胞脂质代谢过程中具有调节作用,而白藜芦醇可激活PPARγ,因此我们推测,白藜芦醇可能通过激活PPARγ抑制AGEs诱导的泡沫细胞形成。此外,由于VSMC钙化和骨细胞分化过程相似,而白藜芦醇可以影响骨细胞分化,我们推测白藜芦醇对AGEs作用下的VSMC钙化也有一定程度的作用。
材料方法
为了证实该推测,本研究将分为体外细胞实验和在体动物实验两部分。
第一部分以人单核细胞系THP-1源性的巨噬细胞为模型,通过检测细胞脂质摄取和转运相关蛋白的表达以及细胞内脂质含量,研究AGEs联合或不联合白藜芦醇对氧化型LDL(ox-LDL)诱导的泡沫细胞形成的影响。第二部分以原代培养的小鼠VSMC为模型,给予适当的条件诱导其向成骨细胞分化,检测相关信号通路和成骨信号分子的表达以及细胞钙含量,观察AGEs联合或不联合白藜芦醇对VSMC钙化的影响。第三部分以apoE基因敲除型小鼠为模型,给予STZ和高脂饮食联合诱导糖尿病动脉粥样硬化模型,给予含白藜芦醇的饲料进行干预,观察其对动物主动脉粥样斑块和钙化的影响。
试验步骤如下:
1.在经PMA诱导的THP-1源性巨噬细胞中加入不同浓度AGEs,以及在固定浓度AGEs作用下加入不同浓度的白藜芦醇,通过免疫印迹检测RAGE的表达变化;
2.通过免疫印迹检测白藜芦醇作用下PPARγ等分子的表达,以及加入PPARγ拮抗剂GW9662后白藜芦醇对RAGE表达的影响;
3.在AGEs和白藜芦醇作用下的巨噬细胞细胞中,检测加入或不加GW9662时CD36、SR-A、ABCA1及ABCG1等相关脂质转运基因的表达情况;
4.通过细胞内总胆固醇定量和油红O染色,检测AGEs、AGEs+白藜芦醇以及AGEs+白藜芦醇+GW9662分别对细胞内胆固醇含量和脂滴形成的影响;
5.通过定量PCR检测不同浓度白藜芦醇对VSMC钙化过程中cbfa1、sm22a和ALP的表达以及细胞钙含量的影响;
6.通过免疫印迹明确白藜芦醇对VSMC中RAGE表达及ERK1/2磷酸化的影响;
7.利用定量PCR和免疫印迹检测白藜芦醇、RAGE中和抗体、ERK1/2阻断剂分别对VSMC中cbfa1和sm22a表达的影响;
8.建立糖尿病动脉粥样硬化小鼠模型,予以白藜芦醇干预20周后测定小鼠体重、血糖、血脂等指标;
9.免疫印迹检测各组小鼠主动脉中RAGE、cbfa1、sm22a的表达情况,验证白藜芦醇对糖尿病小鼠粥样斑块形成和动脉钙化的影响;
10.通过动脉冰冻切片油红O和茜素红染色,观察各组小鼠主动脉粥样硬化和钙化情况。
结果
1. AGEs显著上调巨噬细胞RAGE的表达,而白藜芦醇可以抑制AGEs诱导的RAGE表达上调;PPARγ拮抗剂GW9662可以减弱白藜芦醇对RAGE的抑制作用;
2. AGEs可以上调SR-A的表达,降低ABCA1和ABCG1的表达,而白藜芦醇能够抑制AGEs引起的基因表达变化,但白藜芦醇的作用可被GW9662阻断;
3. AGEs显著升高巨噬细胞中总胆固醇含量,促进脂滴形成;白藜芦醇能显著抑制AGEs引起的脂质蓄积,GW9662可以阻断白藜芦醇的效应;
4.在VSMC中,白藜芦醇显著抑制AGEs诱导的cbfa1表达上调、细胞内ALP和钙含量增加,同时抑制AGEs引起的sm22a的表达降低;
5. AGEs上调VSMC中RAGE的表达,促进ERK1/2磷酸化,而白藜芦醇可以抑制AGEs的作用;
6.加入RAGE中和抗体和ERK1/2抑制剂后,同样可以抑制AGEs诱导的cbfa1表达上调和sm22a表达下降,提示RAGE和ERK1/2介导了白藜芦醇的生物学效应;
7.白藜芦醇可以降低糖尿病小鼠血浆中总胆固醇、甘油三酯及LDL-C含量,升高HDL-C水平,从而部分恢复糖尿病引起的脂质代谢紊乱;
8.白藜芦醇可以抑制糖尿病小鼠主动脉中RAGE、cbfa1的表达,上调PPARγ和sm22a的表达;同时白藜芦醇可以抑制糖尿病小鼠主动脉中粥样硬化斑块和动脉钙化斑块形成。
结论:
1.白藜芦醇通过激活PPARγ抑制RAGE表达,调控SR-A、ABCA1和ABCG1等脂质转运基因,减轻AGEs诱导的巨噬细胞内脂质蓄积,抑制泡沫细胞形成,从而抑制糖尿病apoE敲除小鼠动脉粥样硬化斑块形成。
2.白藜芦醇通过抑制RAGE-ERK1/2通路,抑制AGEs诱导的血管平滑肌细胞钙化,从而减轻糖尿病apoE敲除小鼠的主动脉钙化。
Diabetes is associated with high frequency and high severity of atherosclerosis and vascular calcification which causes most morbidity and mortality in diabetic patients. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and vascular calcification for developing therapeutic options.
Diabetic patients have increased production and reduced clearance of advanced glycation end products (AGEs). It has been well documented that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of cardiovascular disease due to oxidative stress and inflammatory responses. Furthermore, impaired macrophage lipid metabolism directly participates in the foam cell formation in diabetes. In another hand, previous studies found that AGEs increased the osteoblastic trans-differentiation of vascular smooth muscle cell (VSMC). However, these studies were inconsistent and whether the macrophage lipid accumulation and VSMC calcification was actually affected by RAGE activation was still unclear.
Resveratrol (trans-3,5,4’-trihydroxystilbene, RESV), a natural polyphenol phytoalexin, possesses various bioactivities. A recent study indicated that resveratrol inhibits foam cell formation via suppression of reactive oxygen species (ROS) generation and macrophage activation. However, it’s still unknown whether resveratrol could prevent the impairment of AGE on the lipid homeostasis in macrophages, which might partially contribute to the prevention of diabetic atherosclerosis. Furthermore, resveratrol could regulate the differentiation of osteoblast in skeletal. Considering that osteoblast differentiation and VSMC calcification share a lot of similarites, it is possible that resveratol may regulate the VSMC calcification in diabetic patients.
To test the above hypothesis, we first find that resveratrol down-regulates RAGE expression and prevents the impairment of AGEs on macrophage lipid homeostasis through PPARγactivation. Then we document that resveratrol inhibits the AGEs-induced calcification of VSMC by suppression of AGEs-RAGE-ERK1/2 pathway. Finally, the cardiovascular protective effects of resveratol were validated in diabetic apoE knockout (apoE-/-) mice in vivo.
Materials and Methods:
The present study includes in vivo and in vitro experiments. In vivo models include apoE-/- mouse and STZ-induced-diabetic apoE-/- mouse fed with or without resveratrol. In vitro experiments were carried out in THP-1 derived macrophages and in VSMC primarily cultured from the aortas of C57BL/6J mice.
1. The effects of different concentrations of AGEs on RAGE expression and cholesterol accumulation in macrophages were detected by western blot and fluorometric assay respectively.
2. The effect of resveratrol on AGEs-induced protein expression of RAGE, SR-A, ABCA1 and ABCG1 was detected by immunoblotting.
3. The effect of resveratrol on AGEs-induced acceleration of cholesterol accumulation and foam cell formation were detected by fluorometric assay and Oil-Red O staining.
4. The effects of different concentrations of resveratrol on cbfa1 and sm22a expression in VSMC were detected by Real-time PCR.
5. The ALP expression and calcium accumulation in VSMC were detected with specific assay kits.
6. The effect of resveratrol on AGEs-induced RAGE expression and ERK1/2 phosphorylation in VSMC were detected by immunoblotting.
7. The effects of resveratrol, anti-RAGE antibody and ERK1/2 inhibitor on the mRNA expression of cbfa1 and sm22a were detected by real-time PCR.
8. Diabetic atherosclerotic mice models were established by treating apoE-/- mice with STZ and high-fat diet.
9. Blood levels of glucose and lipids were detected by specific assay kits.
10. The calcificaton of VSMC and aortas were shown by alizarin red staining.
Results:
1. AGE promotes cholesterol accumulation through induction of RAGE in macrophages.
2. Resveratrol reduces AGEs-induced RAGE expression via activation of PPARγbut not PPARαnor AMPK.
3. Resveratrol reverses the effect of AGEs on the expression of proteins involved in lipid homeostasis via PPARγactivation.
4. Resveratrol prevents the AGEs-induced acceleration of cholesterol accumulation and inhibits foam cell formation via PPARγ.
5. Resveratrol inhibits AGEs-induced expression of cbfa1 and ALP, upregulates sm22a expression, and attenuates calcium accumulation in VSMC.
5. Resveratrol reduces AGEs-induced RAGE expression and ERK1/2 phosphorylation in VSMC.
6. Blocking RAGE and ERK1/2 pathway mimics the protective effect of resveratrol on AGEs-induced calcification in VSMC.
7. Dietary resveratrol lowers the levels of plasma lipids in diabetic apoE-/- mice.
8. Long-term intervention with resveratrol reduces atherosclerotic lesions and artery tunica media calcification in diabetic apoE-/- mice.
Conclusions:
1. Resveratrol inhibits AGEs-induced foam cell formation through regulating lipid transport in macrophages by suppressing RAGE expression and reduces atherosclerotic lesions in diabetic apoE-/- mice.
2. Resveratrol suppresses AGEs-induced calcification of VSMC through the inhibition of RAGE-ERK1/2 pathway and ameliorates artery tunica media calcification in diabetic apoE-/- mice.
引文
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3. Obayashi, H., et al., Formation of crossline as a fluorescent advanced glycation end product in vitro and in vivo. Biochem Biophys Res Commun, 1996. 226(1): p. 37-41.
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6. Isoda, K., et al., vip AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL. Atherosclerosis, 2007. 192(2): p. 298-304.
7. Iwashima, Y., et al., vip Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages. Biochem Biophys Res Commun, 2000. 277(2): p. 368-80.
8. You, H., et al., Advanced oxidation protein products induce vascular calcification by promoting osteoblastic trans-differentiation of smooth muscle cells via oxidative stress and ERK pathway. Ren Fail, 2009. 31(4): p. 313-9.
9. Sutra, T., et al., Superoxide production: a procalcifying cell signalling event in osteoblastic differentiation of vascular smooth muscle cells exposed to calcificationmedia. Free Radic Res, 2008. 42(9): p. 789-97.
10. Wang, F.S., et al., Superoxide mediates shock wave induction of ERK-dependent osteogenic transcription factor (CBFA1) and mesenchymal cell differentiation toward osteoprogenitors. J Biol Chem, 2002. 277(13): p. 10931-7.
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13. Sadruddin, S. and R. Arora, Resveratrol: biologic and therapeutic implications. J Cardiometab Syndr, 2009. 4(2): p. 102-6.
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