C-peptide activates AMPKα and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes.
C-peptide activates AMPKα and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes.
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作者：
Bhatt MP;Lim YC;Kim YM;Ha KS
血管病变是糖尿病的一种主要并发症；然而，介导血管病变发展的分子机制以及潜在的预防策略尚未明确。我们先前曾报道，C肽通过抑制活性氧（ROS）介导的内皮细胞凋亡来预防糖尿病血管病变。为了进一步深入了解糖尿病血管病变的ROS依赖性机制及其预防方法，我们研究了高糖诱导的胞质和线粒体ROS产生以及其对线粒体动力学改变和细胞凋亡的影响。对于治疗策略，我们利用人脐静脉内皮细胞和糖尿病小鼠的主动脉，通过腺苷酸活化蛋白激酶α（AMPKα）通路研究了C肽对高糖诱导的内皮损伤的血管保护机制。高糖（33 mmol/L）通过一种涉及胞质和线粒体ROS产生之间相互调节的机制增加细胞内ROS。C肽（1 nmol/L）对AMPKα的激活抑制了高糖诱导的ROS产生、线粒体分裂、线粒体膜电位崩溃以及内皮细胞凋亡。此外，AMPK激活剂5 - 氨基咪唑 - 4 - 甲酰胺1 - β - D - 呋喃核糖苷和降糖药二甲双胍模拟了C肽的保护作用。C肽替代疗法使糖尿病小鼠主动脉中高糖诱导的AMPKα去磷酸化、ROS产生以及线粒体紊乱恢复正常。这些发现强调了一种新的机制，即C肽通过该机制激活AMPKα并防止高糖诱导的血管病变。
Vasculopathy is a major complication of diabetes; however, molecular mechanisms mediating the development of vasculopathy and potential strategies for prevention have not been identified. We have previously reported that C-peptide prevents diabetic vasculopathy by inhibiting reactive oxygen species (ROS)-mediated endothelial apoptosis. To gain further insight into ROS-dependent mechanism of diabetic vasculopathy and its prevention, we studied high glucose–induced cytosolic and mitochondrial ROS production and its effect on altered mitochondrial dynamics and apoptosis. For the therapeutic strategy, we investigated the vasoprotective mechanism of C-peptide against hyperglycemia-induced endothelial damage through the AMP-activated protein kinase α (AMPKα) pathway using human umbilical vein endothelial cells and aorta of diabetic mice. High glucose (33 mmol/L) increased intracellular ROS through a mechanism involving interregulation between cytosolic and mitochondrial ROS generation. C-peptide (1 nmol/L) activation of AMPKα inhibited high glucose–induced ROS generation, mitochondrial fission, mitochondrial membrane potential collapse, and endothelial cell apoptosis. Additionally, the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside and the antihyperglycemic drug metformin mimicked protective effects of C-peptide. C-peptide replacement therapy normalized hyperglycemia-induced AMPKα dephosphorylation, ROS generation, and mitochondrial disorganization in aorta of diabetic mice. These findings highlight a novel mechanism by which C-peptide activates AMPKα and protects against hyperglycemia-induced vasculopathy.
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影响因子：
4.1
作者：
Sanders, Matthew J.;Grondin, Pascal O.;Carling, David
通讯作者：
Carling, David
影响因子：
56.9
作者：
Ido, Y;Vindigni, A;Williamson, JR
通讯作者：
Williamson, JR
影响因子：
4.8
作者：
Eid, Assaad A.;Ford, Bridget M.;Abboud, Hanna E.
通讯作者：
Abboud, Hanna E.
DOI：
10.1161/atvbaha.107.155762
发表时间：
2007-12-01
影响因子：
8.7
作者：
Ceolotto, Giulio;Gallo, Alessandra;Avogaro, Angelo
通讯作者：
Avogaro, Angelo
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi