Abstract
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 quantified 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), endothelial‐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 activation. The findings will aid in shaping the rational drug development process for the prevention of ischemic heart disease, especially in females.
Highlights
Myocardial infarction (MI) and cardiac ischemia/reperfusion injury (IRI), two different manifestations of ischemic heart disease, occupy the major share of the cardiovascular disease, which is the leading global cause of mortality and morbidity (Writing Group Members, 2016)
It was noted that IR injury causes cell death and enhancement of ischemic lesion due to the raise in oxidative radicals, poor Ca2+ homeostasis, enhanced mitochondrial transition pore (MTP) opening and mitochondrial failure (Webster 2012)
Angiogenesis/neovascularization following IR injury is crucial in the regulation of infarct size and cardiac remodeling, which are the key determinants of clinical outcome after the heart attacks
Summary
Myocardial infarction (MI) and cardiac ischemia/reperfusion injury (IRI), two different manifestations of ischemic heart disease, occupy the major share of the cardiovascular disease, which is the leading global cause of mortality and morbidity (Writing Group Members, 2016). During MI, blockade of the major coronary arteries that nourish myocardium results in ischemic myocardium leading to myocardial tissue death, thinning of the ventricle walls, fibrosis and heart failure. Failure of mitochondrial function has been identified as one of the key mechanisms in the causation of IRmediated myocardial damage/death (Hausenloy and Yellon 2013; Ong et al 2015). Heightened oxidative stress and calcium overload gained prominence during IRmediated mitochondrial fragmentation and failure, which, if not stopped, leads to myocardial cell death (Ong et al 2010; Kalogeris et al 2012; Disatnik et al 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
