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

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.

Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo

“…The total number of animals used for ARCM isolations was 143. Exclusion criteria were (I) low viability (<50%) on the day of isolation and (II) low viability on day one of culturing (<50%) in accordance with our previous studies [7,72]. The number of excluded isolations due to criterion (I) was 66 and 18 due to criterion (II).…”

“…To assess the autofluorescence of rosiglitazone, all applied drug concentrations were measured in DPBS, and no signal was detected. Therefore, the viability assay results were not influenced by the treatment with rosiglitazone [71][72][73]. For the ARCMs shown in Figure 6a, the normoxia (N) + vehicle group was set to 100% relative fluorescent units (RFU), and all of the data were normalized to the averaged simulated ischemia (SI)+ vehicle group.…”

Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure

“…In the current study, somatostatin was positively associated with the primary endpoint in men, but inversely associated in women. Previous studies have shown that somatostatin exerts a cardioprotective effect in in vitro and animal models of ischemia/reperfusion injury [ 34 ], whereas increased concentrations were associated with a higher mortality risk in patients with advanced HF[ 35 ]. Higher circulating somatostatin levels have been linked to male sex in the general population [ 36 ].…”

The Role of Receptor–Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors

“…In the pancreas, the presence of SSTR1 receptors has been observed in α-cells secreting glucagon and δ-cells secreting somatostatin [ 26 , 27 ]. The presence of SSTR1 receptors in the heart and blood vessels suggests that somatostatin may be involved in the regulation of cardiac and vasomotor functions [ 28 ].…”