The gastrointestinal peptide obestatin induces vascular relaxation via specific activation of endothelium‐dependent NO signalling

Abstract

BACKGROUND AND PURPOSE Obestatin is a recently discovered gastrointestinal peptide with established metabolic actions, which is linked to diabetes and may exert cardiovascular benefits. Here we aimed to investigate the specific effects of obestatin on vascular relaxation. EXPERIMENTAL APPROACH Cumulative relaxation responses to obestatin peptides were assessed in rat isolated aorta and mesenteric artery (n≥ 8) in the presence and absence of selective inhibitors. Complementary studies were performed in cultured bovine aortic endothelial cells (BAEC). KEY RESULTS Obestatin peptides elicited concentration‐dependent relaxation in both aorta and mesenteric artery. Responses to full‐length obestatin(1–23) were greater than those to obestatin(1–10) and obestatin(11–23). Obestatin(1–23)‐induced relaxation was attenuated by endothelial denudation, l‐NAME (NOS inhibitor), high extracellular K+, GDP‐β‐S (G‐protein inhibitor), MDL‐12,330A (adenylate cyclase inhibitor), wortmannin (PI3K inhibitor), KN‐93 (CaMKII inhibitor), ODQ (guanylate cyclase inhibitor) and iberiotoxin (BKCa blocker), suggesting that it is mediated by an endothelium‐dependent NO signalling cascade involving an adenylate cyclase‐linked GPCR, PI3K/PKB, Ca2+‐dependent eNOS activation, soluble guanylate cyclase and modulation of vascular smooth muscle K+. Supporting data from BAEC indicated that nitrite production, intracellular Ca2+ and PKB phosphorylation were increased after exposure to obestatin(1–23). Relaxations to obestatin(1–23) were unaltered by inhibitors of candidate endothelium‐derived hyperpolarizing factors (EDHFs) and combined SKCa/IKCa blockade, suggesting that EDHF‐mediated pathways were not involved. CONCLUSIONS AND IMPLICATIONS Obestatin produces significant vascular relaxation via specific activation of endothelium‐dependent NO signalling. These actions may be important in normal regulation of vascular function and are clearly relevant to diabetes, a condition characterized by endothelial dysfunction and cardiovascular complications.

Vascular Effects of Obestatin in Lean and Obese Subjects

“…The specificity of this effect of obestatin as an NO-related vasodilator in the human circulation is strengthened by the results obtained with infusion of an established endothelium-dependent vasodilator, such as acetylcholine, whose effects substantially mimicked those of obestatin in both lean and obese participants. In this regard, our findings are in close agreement with the observations made by Agnew et al (9) in isolated vessel preparations of rat aorta and mesenteric artery, where obestatin elicits relaxation attenuated by endothelial denudation and NO synthase inhibition but is unaltered by inhibition of endothelium-derived hyperpolarization. Indirect support to a role of obestatin as a vasodilator in humans also stems from an association study showing that circulating levels of obestatin bear an inverse relationship with blood pressure values in insulin-resistant patients (16).…”

“…Each participant then received incremental doses of obestatin (Bachem AG, Weil am Rhein, Germany) from 0.2 to 3.2 nmol/min. These doses were selected to achieve intravascular concentrations of the peptide similar to those previously shown to induce relaxation in arterial preparations in vitro (9). Each dose of obestatin was given for 5 min, and venous samples and flow measurements were obtained at the end of each period.…”

“…Thus, in rat aorta and the superior mesenteric artery, Agnew et al (9) have demonstrated that obestatin favorably affects endothelial function, inducing nitric oxide (NO)-dependent relaxation via an adenylate cyclase-linked GPCR. These findings have been more recently confirmed in the mouse cerebral artery, where obestatin induces NO-dependent vasodilation, which is maintained during ghrelin receptor antagonism (10).…”

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

“…Low level of plasma obestatin could be associated with early atherosclerosis in T2DM patients [388]. Obestatin exerts vascular relaxation via activation of specific endotheliumdependent NO signaling pathways [389]. Obestatin actions are still to be fully elucidated in many organ tissues.…”

Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway

“…These peptides have been shown to modulate cardiac inotropism 5, 6, 7, 8 and vascular tone 9, 10, 11, 12, 13, 14, and to reduce cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R) 15, 16, 17.…”