Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during
ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of
protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute
myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac
troponin I (cTnI), a key sarcomeric
protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight
amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of
myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced
mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after
myocardial infarction.