Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection

Imre Vörös; Éva Sághy; Krisztina Pohóczky; András Makkos; Zsófia Onódi; Gábor B Brenner; Tamás Baranyai; Bence Ágg; Barnabás Váradi; Ágnes Kemény; Przemyslaw Leszek; Anikó Görbe; Zoltán V Varga; Zoltán Giricz; Rainer Schulz; Zsuzsanna Helyes; Péter Ferdinandy

doi:10.3389/fphar.2021.663655

Somatostatin and Its Receptors in Myocardial Ischemia/Reperfusion Injury and Cardioprotection

Front Pharmacol. 2021 Nov 5:12:663655. doi: 10.3389/fphar.2021.663655. eCollection 2021.

Authors

Imre Vörös^{1

2}, Éva Sághy¹, Krisztina Pohóczky^{3

4

5}, András Makkos^{1

6}, Zsófia Onódi^{1

2}, Gábor B Brenner^{1

6}, Tamás Baranyai¹, Bence Ágg^{1

6

7}, Barnabás Váradi¹, Ágnes Kemény^{4

5

8}, Przemyslaw Leszek⁹, Anikó Görbe^{1

6}, Zoltán V Varga^{1

2}, Zoltán Giricz^{1

6}, Rainer Schulz¹⁰, Zsuzsanna Helyes^{4

5}, Péter Ferdinandy^{1

6}

Affiliations

¹ Cardiometabolic Research Group and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
² HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary.
³ Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Pécs, Hungary.
⁴ Szentágothai János Research Center, University of Pécs, Pécs, Hungary.
⁵ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
⁶ Pharmahungary Group, Szeged, Hungary.
⁷ Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁸ Department of Medical Biology, University of Pécs, Pécs, Hungary.
⁹ Department of Heart Failure and Transplantology, Cardinal Stefan Wyszyński National Institute of Cardiology, Warszawa, Poland.
¹⁰ Institute of Physiology, Justus-Liebig-University Giessen, Giessen, Germany.

Abstract

Little is known about the role of the neuropeptide somatostatin (SST) in myocardial ischemia/reperfusion injury and cardioprotection. Here, we investigated the direct cardiocytoprotective effect of SST on ischemia/reperfusion injury in cardiomyocyte cultures, as well as the expression of SST and its receptors in pig and human heart tissues. SST induced a bell-shaped, concentration-dependent cardiocytoprotection in both adult rat primary cardiomyocytes and H9C2 cells subjected to simulated ischemia/reperfusion injury. Furthermore, in a translational porcine closed-chest acute myocardial infarction model, ischemic preconditioning increased plasma SST-like immunoreactivity. Interestingly, SST expression was detectable at the protein, but not at the mRNA level in the pig left ventricles. SSTR1 and SSTR2, but not the other SST receptors, were detectable at the mRNA level by PCR and sequencing in the pig left ventricle. Moreover, remote ischemic conditioning upregulated SSTR1 mRNA. Similarly, SST expression was also detectable in healthy human interventricular septum samples at the protein level. Furthermore, SST-like immunoreactivity decreased in interventricular septum samples of patients with ischemic cardiomyopathy. SSTR1, SSTR2, and SSTR5 but not SST and the other SST receptors were detectable at the mRNA level by sequencing in healthy human left ventricles. In addition, in healthy human left ventricle samples, SSTR1 and SSTR2 mRNAs were expressed especially in vascular endothelial and some other cell types as detected by RNA Scope^® in situ hybridization. This is the first demonstration that SST exerts a direct cardiocytoprotective effect against simulated ischemia/reperfusion injury. Moreover, SST is expressed in the heart tissue at the peptide level; however, it is likely to be of sensory neural origin since its mRNA is not detectable. SSTR1 and SSTR2 might be involved in the cardioprotective action of SST, but other mechanisms cannot be excluded.

Keywords: gene expression; ischemia-reperfusion; ischemic conditioning; myocardial infarction; somatostatin; somatostatin receptor; translational research.