Suppression of soluble adenylyl cyclase protects smooth muscle cells against oxidative stress-induced apoptosis

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• 作者：Sanjeev Kumar (1)
  Avinash Appukuttan (1)
  Abdelouahid Maghnouj (2)
  Stephan Hahn (2)
  H. Peter Reusch (1)
  Yury Ladilov (1) (3)
  
• 关键词：Soluble adenylyl cyclase ; Apoptosis ; Smooth muscle cells ; Mitochondria ; ROS ; P38
• 刊名：Apoptosis
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：19
• 期：7
• 页码：1069-1079
• 全文大小：
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• 作者单位：Sanjeev Kumar (1)
  Avinash Appukuttan (1)
  Abdelouahid Maghnouj (2)
  Stephan Hahn (2)
  H. Peter Reusch (1)
  Yury Ladilov (1) (3)
  
  1. Department of Clinical Pharmacology, Ruhr-University Bochum, Universit?tsstrasse 150, 44801, Bochum, Germany
  2. Department of Molecular Gastroenterology-Oncology, Ruhr-University Bochum, Bochum, Germany
  3. Center for Cardiovascular Research, Charite, Berlin, Germany
  
• ISSN：1573-675X

文摘

Apoptosis of vascular smooth muscle cells (VSMC) significantly contributes to the instability of advanced atherosclerotic plaques. Oxygen radicals are an important cause for VSMC death. However, the precise mechanism of oxidative stress-induced VSMC apoptosis is still poorly understood. Here, we aimed to analyse the role of soluble adenylyl cylclase (sAC). VSMC derived from rat aorta were treated with either H2O2 (300?μmol/L) or DMNQ (30?μmol/L) for 6?h. Oxidative stress-induced apoptosis was prevented either by treatment with 30?μmol/L KH7 (a specific inhibitor of sAC) or by stable sAC-knockdown (shRNA-transfection). A similar effect was found after inhibition of protein kinase A (PKA). Suppression of the sAC/PKA-axis led to a significant increase in phosphorylation of the p38 mitogen-activated protein kinase under oxidative stress accompanied by a p38-dependent phosphorylation/inactivation of the pro-apoptotic Bcl-2-family protein Bad. Pharmacological inhibition of p38 reversed these effects of sAC knockdown on apoptosis and Bad phosphorylation, suggesting p38 as a link between sAC and apoptosis. Analysis of the protein phosphatases 1 and 2A activities revealed an activation of phosphatase 1, but not phosphatase 2A, under oxidative stress in a sAC/PKA-dependent manner and its role in controlling the p38 phosphorylation. Inhibition of protein phosphatase 1, but not 2A, prevented the pro-apoptotic effect of?oxidative stress. In conclusion, sAC/PKA-signaling plays a key role in the oxidative stress-induced apoptosis of VSMC. The cellular mechanism consists of the sAC-promoted and protein phosphatase 1-mediated suppression of p38 phosphorylation resulting to activation of the mitochondrial pathway of apoptosis.