Decreased Myocardial Injury and Improved Contractility After Administration of a Peptide Derived Against the Alpha-Interacting Domain of the L-Type Calcium Channel

Background-Myocardial infarction remains the leading cause of morbidity and mortality associated with coronary artery disease. The L-type calcium channel (ICa-L) is critical to excitation and contraction. Activation of the channel also alters mitochondrial function. Here, we investigated whether application of a alpha-interacting domain/transactivator of transcription (AID-TAT) peptide, which immobilizes the auxiliary beta(2) subunit of the channel and decreases metabolic demand, could alter mitochondrial function and myocardial injury. Methods and Results-Treatment with AID-TAT peptide decreased ischemia-reperfusion injury in guinea-pig hearts ex vivo (n=11) and in rats in vivo (n=9) assessed with uptake of nitroblue tetrazolium, release of creatine kinase, and lactate dehydrogenase. Contractility (assessed with catheterization of the left ventricle) was improved after application of AID-TAT peptide in hearts ex vivo (n=6) and in vivo (n=8) up to 12 weeks before sacrifice. In search of the mechanism for the effect, we found that intracellular calcium ([Ca2+](i), Fura-2), superoxide production (dihydroethidium fluorescence), mitochondrial membrane potential (psi(m), JC-1 fluorescence), reduced nicotinamide adenine dinucleotide production, and flavoprotein oxidation (autofluorescence) are decreased after application of AID-TAT peptide. Conclusions-Application of AID-TAT peptide significantly decreased infarct size and supported contractility up to 12 weeks postcoronary artery occlusion as a result of a decrease in metabolic demand during reperfusion.