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.
Bibliographical noteFunding Information:
This research was funded by AHA Postdoctoral Fellowship (19POST34380299) to A.J.L., FAPESP (2018/18627-3) to J.C.B.F., and NIH grant (R01-HL52141) to D.M.-R.We appreciate the informative discussions and generosity of the members of the Mochly-Rosen laboratory. Schematic (Figure 2C) and graphical abstract created by Lucia Lee with BioRender.
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
- Cardiac ischemia-reperfusion injury
- Cardiac troponin I