Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation.
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-R1a 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+/-0.23nM, B(max) 5848+/-291fmol/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 4.25nM. 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.
Rossi
Fabio
F
Dipartimento di Fisiopatologia Medica, Sapienza Università di Roma, Rome, Italy.
Castelli
Antonella
A
Bianco
Maria J
MJ
Bertone
Cora
C
Brama
Marina
M
Santiemma
Vittorio
V
D001011:Aorta / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000473:pathology*; D054440:Receptors, Ghrelin / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054439:Ghrelin; D054440:Receptors, Ghrelin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases