These authors contributed equally.
Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure
Article first published online: 24 OCT 2011
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Journal of Cellular and Molecular Medicine
Volume 15, Issue 11, pages 2443–2451, November 2011
How to Cite
Lim, S. Y., Hausenloy, D. J., Arjun, S., Price, A. N., Davidson, S. M., Lythgoe, M. F. and Yellon, D. M. (2011), Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure. Journal of Cellular and Molecular Medicine, 15: 2443–2451. doi: 10.1111/j.1582-4934.2010.01235.x
- Issue published online: 24 OCT 2011
- Article first published online: 24 OCT 2011
- Accepted manuscript online: 9 DEC 2010 06:38AM EST
- Received: August 6, 2010; Accepted: December 7, 2010
- heart failure;
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.