Abstract
BackgroundIn the presence of comorbidities the effectiveness of many cardioprotective strategies is blunted. The goal of this study was to assess in a hypertensive rat model if the early reperfusion with anti-hypertensive and pro-angiogenic Chromogranin A-derived peptide, Catestatin (CST:hCgA352–372; CST-Post), protects the heart via Reperfusion-Injury-Salvage-Kinases (RISK)-pathway activation, limiting infarct-size and apoptosis, and promoting angiogenetic factors (e.g., hypoxia inducible factor, HIF-1α, and endothelial nitric oxide synthase, eNOS, expression).Methods and ResultsThe effects of CST-Post on infarct-size, apoptosis and pro-angiogenetic factors were studied in isolated hearts of spontaneously hypertensive rats (SHR), which underwent the following protocols: (a) 30-min ischemia and 120-min reperfusion (I/R); (b) 30-min ischemia and 20-min reperfusion (I/R-short), both with and without CST-Post (75 nM for 20-min at the beginning of reperfusion). In unprotected Wistar-Kyoto hearts, used as normal counterpart, infarct-size resulted smaller than in SHR. CST-Post reduced significantly infarct-size and improved post-ischemic cardiac function in both strains. After 20-min reperfusion, CST-Post induced S-nitrosylation of calcium channels and phosphorylation of RISK-pathway in WKY and SHR hearts. Yet specific inhibitors of the RISK pathway blocked the CST-Post protective effects against infarct in the 120-min reperfusion groups. Moreover, apoptosis (evaluated by TUNEL, ARC and cleaved caspase) was reduced by CST-Post. Importantly, CST-Post increased expression of pro-angiogenetic factors (i.e., HIF-1α and eNOS expression) after two-hour reperfusion.ConclusionsCST-Post limits reperfusion damages and reverses the hypertension-induced increase of I/R susceptibility. Moreover, CST-Post triggers antiapoptotic and pro-angiogenetic factors suggesting that CST-Post can be used as an anti-maladaptive remodeling treatment.
Highlights
The presence of comorbidities including hypertension and myocardial hypertrophy has been reported to blunt the efficacy of cardioprotective protocols such as ischemic postconditioning (IPostC) and to alter expression and responsiveness of several kinases, including those involved in the so-called ReperfusionInjury-Salvage-Kinases (RISK)-pathway [1,2,3,4]
We confirmed that CST was able to reduce Infarct size (IS) in WKY hearts and that, in the ischemia and 120-min reperfusion (I/R) group of spontaneously hypertensive rats (SHR) hearts, the IS was larger (70611% of risk area) as compared to WKY group (Fig. 2, panel A)
The co-infusion with WN, an inhibitor of PI3K/Akt or CHE, an inhibitor of PKC, blocked the protective effects of CST-Post in SHR (IS was 5462% and 6262% respectively, p,0.05 vs. SHR_CST-Post, and p = NS vs. SHR_I/R for both) (Fig. 2, panel B); similar results were observed for normal hearts [16]
Summary
The presence of comorbidities including hypertension and myocardial hypertrophy has been reported to blunt the efficacy of cardioprotective protocols such as ischemic postconditioning (IPostC) and to alter expression and responsiveness of several kinases, including those involved in the so-called ReperfusionInjury-Salvage-Kinases (RISK)-pathway [1,2,3,4]. Given the antiapoptotic and pro-angiogenetic properties of CST in normotensive rats, we hypothesize that CST would slow-down apoptosis and augment the expression of the early pro-angiogenetic factor, namely hypoxia-inducible factor-1 (HIF-1a) [22,23] in SHR, i.e., a polygenic-model of rodent hypertension [24] The involvement of HIF-1a is of relevance, due to its central role in preconditioning [22,23] and its redox sensitive expression [22]. The goal of this study was to assess in a hypertensive rat model if the early reperfusion with anti-hypertensive and pro-angiogenic Chromogranin A-derived peptide, Catestatin (CST:hCgA352–372; CST-Post), protects the heart via Reperfusion-Injury-SalvageKinases (RISK)-pathway activation, limiting infarct-size and apoptosis, and promoting angiogenetic factors (e.g., hypoxia inducible factor, HIF-1a, and endothelial nitric oxide synthase, eNOS, expression)
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