Background:
Somatostatin, a well-known inhibitory peptide, regulates hormone release, neurotransmission, and cell proliferation through its five G protein-coupled receptors (SSTR1–5). While SSTRs are implicated in endocrine and inflammatory processes, their expression in the human heart, particularly in the context of heart failure, remains poorly understood. This study aimed to characterize the somatostatin receptor profile in failing human hearts to unravel mechanisms underlying cardiac dysfunction and identify potential therapeutic targets for heart failure.
Methods:
Non-failing heart tissues were sourced from the Tissue Collection Center at the University of Szeged, Hungary, and biopsies from failing hearts were obtained at Immanuel University Hospital Brandenburg (Bernau bei Berlin). Ethical approval was granted by both institutions. The expression of SSTRs was analyzed by immunohistochemistry on cryosections, and human cardiac microvascular endothelial cells were isolated from these tissues for further examination via PCR. Additionally, human umbilical vein endothelial cells (HUVECs) were employed to assess receptor expression under basal conditions and following TNFα treatment. Endothelial migration was evaluated using a wound healing assay.
Results:
Healthy cardiac tissues exhibited strong expression of SSTR1 and SSTR5 (n=5, p<0.05 for all subsequent experiments) and moderate expression of SSTR3, predominantly localized within cardiac vessels. Notably, SSTR2 and SSTR4 were not detectable. In contrast, failing hearts displayed significant reductions in SSTR1, SSTR3, and SSTR5 expression, alongside de novo expression of SSTR2, while SSTR4 remained absent. These findings were corroborated by PCR analysis in endothelial cells. Similarly, HUVECs expressed SSTR1 and SSTR5 under basal conditions; however, TNFα treatment resulted in the downregulation of SSTR1 and SSTR5, accompanied by the emergence of SSTR2. This suggests that SSTR2 expression is modulated by inflammatory signals. Treatment of HUVECs with somatostatin amplified VEGF-induced endothelial cell (EC) proliferation, migration, and angiogenesis. To elucidate which receptors mediate these endothelial effects, SSTR1, SSTR2, and SSTR5 were selectively overexpressed using lentiviral particles. Overexpression of SSTR5 robustly enhanced VEGF- and FCS-induced EC proliferation and migration. Conversely, overexpression of SSTR2 significantly suppressed VEGF- and FCS-induced EC proliferation and migration. Overexpression of SSTR1 exhibited a weak pro-proliferative and pro-migratory effect on ECs.
Conclusion:
This study reveals a distinct alteration in the SSTR expression profile in failing human hearts, characterized by decreased SSTR1, SSTR3, and SSTR5 and the emergence of SSTR2 expression. Furthermore, the inflammatory modulation observed in HUVECs supports the notion that SSTR2 is inflammation-regulated, appearing predominantly under pathological conditions. These results suggest that the shift in somatostatin receptor patterns may contribute to cardiac dysfunction in heart failure. Notably, the pro-angiogenic role of SSTR5 and the anti-angiogenic effects of SSTR2 highlight these receptors as promising targets for therapeutic intervention, offering new avenues for the treatment of heart failure.
