Mdivi-1 induced acute changes in the angiogenic profile after ischemia-reperfusion injury in female mice

Sudhakar Veeranki, Suresh C Tyagi
Physiological Reports2017
The aim of this study is to determine the effects of mitochondrial division inhibitor 1 (Mdivi-1), the mitochondrial fission inhibitor, on the angiogenic profiles after the ischemia reperfusion injury (IR injury) in female mice. Female mice were treated with Mdivi-1 inhibitor, 2 days prior, on the day of IR injury and 2 days after IR injury, for a period of 5 days. Both control and treatment groups underwent 30 min of ischemia and 72 h of reperfusion. On the day 3, mice were sacrificed and the ischemic and nonischemic portions of heart tissue were collected. Relative levels of 53 angiogenesis-related proteins were quanti- fied simultaneously using Angiogenic arrays. Heart function was evaluated before and after 72 h of IR injury. Mdivi-1 treatment ameliorated IR induced functional deterioration with positive angiogenic profile. The seminal changes include suppression of Matrix metalloproteinase (MMP3), tissue inhibitor of metalloproteases (TIMP1) and chemokine (C-X-C motif) ligand 10 (CXCL10) levels and prevention of connexin 43 (Cx43) loss and downregulation in the antioxidant enzyme levels. These changes are correlated with enhanced endothelial progenitor cell marker (cluster of differentiation (CD31), endothe- lial-specific receptor tyrosine kinase (Tek), fMS-like tyrosine kinase 4 (Flt4) and kinase insert domain protein receptor (Kdr)) presence. Our study is the first to report the role of mitochondrial dynamics in regulation of myocardial IR-induced angiogenic responses. Inhibition of excessive mitochondrial fission after IR injury ameliorated heart dysfunction and conferred positive angiogenic response. In addition, there were improvements in the preservation of Cx43 levels and oxidative stress handling along with suppression of apoptosis activa- tion. The findings will aid in shaping the rational drug development process for the prevention of ischemic heart disease, especially in females. Introduction

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