Abstract 15589: Protein-Protein Inhibitor Peptide of Drp1/Fis1 Interaction Protects the Heart Against Ischemia/Reperfusion Injury
Background: The involvement of mitochondrial function and dynamics in cardiovascular health has been lately been demonstrated. Mitochondrial fission, governed by dynamin related protein 1 (Drp1) was described to be one of the causes of tissue damage induced by IR injury.
Objective: Here we determined whether acute inhibition of excessive mitochondrial fission at the onset of reperfusion improves mitochondrial dysfunction and cardiac contractility post-myocardial infarction.
Methods and Results: We used a selective inhibitor of the fission machinery, P110, which we have recently designed. P110 is a peptide inhibitor that inhibits selectively Fis1/Drp1 interaction. This 7 amino acids peptide represents a homologous sequence between Fis1 and Drp1; that sequence is located in the GTPase domain of Drp1 (DLLPRGT). P110 treatment inhibited the interaction of fission proteins Fis1/Drp1, decreased mitochondrial fission and improved bioenergetics in three different rat models of IR, including primary cardiomyocytes, ex vivo heart model and an in vivo myocardial infarction model. Drp1 transiently bound to the mitochondria following IR injury and P110 treatment blocked Drp1 mitochondrial association. Compared with control treatment, P110 (1 μmol/L) decreased infarct size by 28% and increased ATP levels by 1.7 fold after IR relative to control IR in the ex vivo model (n=6/group). P110 also greatly inhibited excessive mitochondrial fragmentation as determined by electron microscopy. Intraperitoneal injection of P110 (0.5mg/kg) at the onset of reperfusion in an in vivo model improved mitochondrial oxygen consumption by 68% when measured 3 weeks after ischemic injury, improved cardiac fractional shortening by 35%, reduced mitochondrial H2O2 uncoupling state by 70% and improved overall mitochondrial functions. (n=6 rats/group, p<0.05)
Conclusions: We found that acute excessive mitochondrial fission and fragmentation at reperfusion contributes to long-term cardiac dysfunction in rats and that inhibition of mitochondrial fragmentation at the onset of reperfusion is sufficient to result in long-term benefits as evidenced by inhibiting cardiac dysfunction three weeks after acute myocardial infarction.
- © 2013 by American Heart Association, Inc.