A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury

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 (delta PKC) with a pan-inhibitor (delta V1-1) 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 delta PKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, delta PKC (psi TnI), 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 delta PKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/delta PKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.

Automated summary

Inhibition of protein kinase C delta (delta PKC) is shown to protect against myocardial infarction and improve mitochondrial function. Additionally, blocking the interaction between cardiac troponin I (cTnI) and delta PKC can attenuate tissue injury and mitigate IR-induced mitochondrial dysfunction.