Ghrelin (Ghr), the natural ligand of growth hormone secretagogue receptor, is principally produced by the stomach. An interesting aspect in Ghr cardiovascular effects was elicited by the identification of ghrelin and GHS (growth hormone secretagogue) receptor mRNA expression in several cardiovascular tissues and cell types. In man, Ghr administration induced lowering of blood pressure, and decreased plasma levels were reported in several pathological conditions. The present investigation was performed to elucidate ghrelin effect on contraction and proliferation of human aortic smooth muscle cells (HASMC). Ghrelin receptor expression in HASMC was evaluated by RT-PCR, and binding studies were performed to elucidate the receptor kinetics. Ghr effect on angiotensin II-induced HASMC contraction and proliferation was evaluated in vitro. In addition, involvement of cAMP, ERK, and Akt pathways was investigated. PCR documented GHS-Rla expression. Binding of [(125)I-His(9)]-Ghrelin to HASMC was saturable in a dose-dependent manner. Scatchard analysis showed a single class of binding sites (Kd 1.58 +/- 0.23 nM, B(max) 5848 +/- 291 fmol/10(5) cells). In competition binding, (D-Lys(3))-GHRP-6 showed a capacity to compete with [(125)I-His(9)]-Ghrelin with Ki of 4.25 nM. Ghrelin was able to inhibit angiotensin II-induced proliferation and contraction in a dose-response fashion via the cAMP/PKA pathway. Our data document that Ghr affects several HASMC functions, opening the way to consider ghrelin as a possible therapeutic target in many pathological conditions associated with vascular damage and remodelling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation / Fabio, Rossi; Antonella, Castelli; Maria J., Bianco; Cora, Bertone; Marina, Brama; Santiemma, Vittorio. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - STAMPA. - 203:1(2009), pp. 97-104. [10.1016/j.atherosclerosis.2008.06.015]
Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation
SANTIEMMA, Vittorio
2009
Abstract
Ghrelin (Ghr), the natural ligand of growth hormone secretagogue receptor, is principally produced by the stomach. An interesting aspect in Ghr cardiovascular effects was elicited by the identification of ghrelin and GHS (growth hormone secretagogue) receptor mRNA expression in several cardiovascular tissues and cell types. In man, Ghr administration induced lowering of blood pressure, and decreased plasma levels were reported in several pathological conditions. The present investigation was performed to elucidate ghrelin effect on contraction and proliferation of human aortic smooth muscle cells (HASMC). Ghrelin receptor expression in HASMC was evaluated by RT-PCR, and binding studies were performed to elucidate the receptor kinetics. Ghr effect on angiotensin II-induced HASMC contraction and proliferation was evaluated in vitro. In addition, involvement of cAMP, ERK, and Akt pathways was investigated. PCR documented GHS-Rla expression. Binding of [(125)I-His(9)]-Ghrelin to HASMC was saturable in a dose-dependent manner. Scatchard analysis showed a single class of binding sites (Kd 1.58 +/- 0.23 nM, B(max) 5848 +/- 291 fmol/10(5) cells). In competition binding, (D-Lys(3))-GHRP-6 showed a capacity to compete with [(125)I-His(9)]-Ghrelin with Ki of 4.25 nM. Ghrelin was able to inhibit angiotensin II-induced proliferation and contraction in a dose-response fashion via the cAMP/PKA pathway. Our data document that Ghr affects several HASMC functions, opening the way to consider ghrelin as a possible therapeutic target in many pathological conditions associated with vascular damage and remodelling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.