Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis

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• 作者：Brittany A. Potz ; MD ; Ashraf A. Sabe ; MD ; Nassrene Y. Elmadhun ; MD ; Richard T. Clements ; PhD ; M. Ruhul Abid ; MD ; PhD ; Neel R. Sodha ; MD ; Frank W. Sellke ; MD ; ^{fsellke@lifespan.org}
• 关键词：calpain inhibition ; chronic myocardial ischemia ; metabolic syndrome ; angiogenesis
• 刊名：The Journal of Thoracic and Cardiovascular Surgery
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：153
• 期：2
• 页码：342-357
• 全文大小：3219 K
• 卷排序：153

文摘

Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3β (GSK-3β) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome.MethodsPigs were fed a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor to the left circumflex artery. Three weeks later, the animals received no drug (high-cholesterol controls [HCC]), a high-dose calpain inhibitor (HCI), a low-dose calpain inhibitor (LCI), or a GSK-3β inhibitor (GSK-3βI). The diets and drug regimens were continued for 5 weeks and the myocardial tissue was harvested.ResultsCalpain and GSK-3β inhibition caused an increase in myocardial perfusion ratios at rest and during pacing compared with controls. Pigs in the LCI and HCI groups had increased vessel density in the ischemic myocardium, and pigs in the GSK-3βI group had increased vessel density in the ischemic and nonischemic myocardium compared with the HCC group. Calpain inhibition modulates proteins involved in the insulin/PI3K and WNT/β-catenin pathways. Quantitative proteomics revealed that calpain and GSK-3β inhibition significantly modulated the expression of proteins enriched in cytoskeletal regulation, metabolism, respiration, and calcium-binding pathways.ConclusionsIn the setting of metabolic syndrome, calpain or GSK-3β inhibition increases vessel density in both ischemic and nonischemic myocardial tissue. Calpain inhibition may exert these effects through the inhibition of GSK-3β and up-regulation of downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways.