Catestatin increases the expression of anti-apoptotic and pro-angiogenetic factors in the post-ischemic hypertrophied heart of SHR.

Abstract

BACKGROUND:

In 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 RESULTS:

The 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.

CONCLUSIONS:

CST-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.

• Authors: Claudia Penna, Teresa Pasqua, Daniela Amelio, Maria-Giulia Perrelli, Carmelina Angotti, Francesca Tullio, Sushil K Mahata, Bruno Tota, Pasquale Pagliaro, Maria C Cerra, Tommaso Angelone
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e102536 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25099124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Apoptosis Regulatory Proteins
• Chromogranin A
• Peptide Fragments
• chromogranin A (344-364)

Topics

• Animals
• Apoptosis Regulatory Proteins (biosynthesis)
• Cardiomegaly (drug therapy, metabolism, pathology)
• Chromogranin A (pharmacology)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects)
• Male
• Myocardial Ischemia (drug therapy, metabolism, pathology)
• Myocardium (metabolism, pathology)
• Peptide Fragments (pharmacology)
• Rats
• Rats, Inbred SHR