Cardioprotective effect exerted by catestatin in hypertensive hearts: molecular mechanisms

Catestatin (CST) is a peptide derived by Chromogranin A that exerts cardiovascular effects. While endogenous CST plasma levels are decreased in hypertensive patients and in their offspring, exogenous CST rescues arterial hypertension of CgA knockout mice. Postconditioning (PostC) can be defined as therapeutic interventions in the early phases of reperfusion to limit reperfusion injury. It can be obtained with either a few seconds of intermittent ischemias (ischemic PostC) or with drugs given in the early reperfusion (pharmacological PostC). We have recently demonstrated that CST can induce a PostC-like cardioprotective effect. Both ischemic and pharmacological PostC have been shown to reduce infarct size via pro-survival signaling cascades and post-transcriptional modifications of proteins, such as S-nitrosylation. However, much of these data have been obtained in healthy cohorts; whether PostC-induced protection is maintained in the setting of comorbidities, such as hypertension and cardiac hypertrophy, is largely unexplored. Data obtained in our laboratory showed a reduced effectiveness of ischemic PostC in the presence of hypertension in reducing infarct size. We aimed to assess the consequences of hypertension on the infarct-sparing effect of pharmacological PostC induced by CST (CST-Post). We studied the effects of CST-Post on infarct size and post-ischemic cardiac function in both normotensive (WKY) and in spontaneously hypertensive rats (SHRs). Isolated hearts from WKY and SHRs underwent the following protocols: (a) 30-min ischemia and 120-min reperfusion (I/R); (b) CST-Post (I/R + CST 75nM for 20-min). In order to assess the involvement of kinases involved in cardioprotection, we co-infused specific blockers for PKC (Chelerythrine, CHE) and Akt (Wortmannin, WN) in the presence of CST-Post. Developed left ventricular pressure (dLVP) and infarct size were measured. Infarct size was 47±6% and 68±11% in WKY_I/R and SHR_I/R, respectively. CST-Post reduced infarct size in both strains; in particular in SHRs infarct size was 24±3% (p<0.001 vs SHR_I/R). CST-Post reduced contracture in SHR and WKY. Moreover CST-Post induced a marked recovery of post-ischemic dLVP in both WKY and SHRs. The administration of blockers (CHE and WN) abolished the protective effect of CST-Post. Western blotting analysis confirmed the activation of Akt and PKC in hearts treated with CST-Post. Moreover, the administration of CST-Post in both SHR and WKY induced a significant increase in protein S-nitrosylation. Here, we provide evidence for a protective efficacy of CST-Post in hypertensive conditions, which involves PKC and Akt activation and nitric oxide mediated protein nitrosylation.