Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure

Abstract

The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD–/– mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation. After 2 days, myocardial infarct size was smaller and left ventricular (LV) function was better preserved in CypD–/– mice compared to WT mice. After 28 days, when compared to WT mice, in the CypD–/– mice, mortality was halved, myocardial infarct size was reduced, LV systolic function was better preserved, LV dilatation was attenuated and in the remote non-infarcted myocardium, there was less cardiomyocyte hypertrophy and interstitial fibrosis. Finally, ex vivo fibroblast proliferation was found to be reduced in CypD–/– cardiac fibroblasts, and in WT cardiac fibroblasts treated with the known CypD inhibitors, cyclosporin-A and sanglifehrin-A. Following an MI, mice lacking CypD have less mortality, smaller infarct size, better preserved LV systolic function and undergo less adverse LV remodelling. These findings suggest that the inhibition of mitochondrial CypD may be a novel therapeutic treatment strategy for post-MI heart failure.

Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

“…So-called ischemia-reperfusion damage is believed initiated by a burst of oxygen radicals rapidly produced by mitochondria (Kalogeris et al, 2012; Perrelli, 2011), with some similarity to air BM harvest. Induction of the MPTP is implicated in mechanisms of ischemia-reperfusion damage (Griffiths and Halestrap, 1995; Kim et al, 2003; Lim et al, 2010). This may be similar to what HSCs experience upon harvest in ambient air, with induction of the MPTP via oxidative stress.…”

Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-α Cre-Mediated Neuropilin-1 Null Mice

“…Previous studies have shown that mitochondrial dysfunction and reduced ATP production are associated and accelerate the progressive nature of heart failure 22, 23 . Modulation of mitochondrial function reduces the infarct size of the ischemic heart in mice and represents a promising therapeutic strategy for heart failure 24–26 . In this context, our findings suggest that loss of NRP-1 in CMs results in significant alterations in mitochondrial homeostasis, which may be due to altered PGC1α and PPARγ expression and eventually lead to cardiomyopathy and increased heart failure after ischemic stress.…”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…The mPTP inhibitors, such as cyclosporin-A (CsA) (153, 154), cyclophilin-D (155), cinnamic anilides (156), and antioxidants are known to prevent the mPTP opening. Yin et al reported a NP system containing CsA which when used in combination with adipose-derived stem cell (ASCs) in a swine model of myocardial infarction showed therapeutic benefits (157).…”