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

Author(s)

Qvit, Nir ; Lin, Amanda J. ; Elezaby, Aly ; Ostberg, Nicolai P. ; Campos, Juliane C. ; Ferreira, Julio C. B. ; Mochly-Rosen, Daria

• Document type: Journal article
• Source: PHARMACEUTICALS; v. 15, n. 3, p. 11-pg., 2022-03-01.

Abstract

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. (AU)

• FAPESP's process: 18/18627-3 - Mechanisms of exercise-induced mitophagy: a new avenue to drug discovery
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Scholarships abroad - Research