The Protective Role Of Agonists Of Growth Hormone-releasing Hormone In Vascular Calcification

Background and ObjectiveVascular calcification(VC)is an independent risk factor for morbidity and mortality in patients with atherosclerosis,diabetes mellitus and chronic kidney disease.Hormones such as Estrogen and Parathyroid Hormone are involved in development of VC.Here,we investigated the effect of an agonist of growth hormone-releasing hormone(GHRH-A),MR409,on smooth muscle cells(SMCs)and the protective role of GHRH-A on VC in osteoprotegerin deficient(OPG-/-)mouse.ResultsGHRH receptor and its variant,SV1,were detected in aortic SMCs isolated from both human and wild type C57BL/6 mice.Calcification on cultured SMCs was induced with ?-glycerophosphoric acid(Pi)in the presence or absence of MR409.There were significantly fewer calcific nodules and less calcium on SMCs cultured with MR409 than those without MR409,as measured by Alirazin Red staining and calcium quantification.The anti-calcificaiton effect of MR409 was partially blocked by a GHRH antagonist,MIA602.Cytosolic cAMP was elevated and NADPH oxidase activity and production of reactive oxygen species(ROS)in SMCs were significantly reduced with treatment of MR409.Alkaline phosphatase activity in MR409-treated SMCs was also lower.Runx2,a key trancription factor in osteogenesis,was downregulated in treated group with MR409 at both mRNA and protein levels.In osteoprotegerin deficient(OPG-/-)mice that spontaneously develop VC,subcutaneous injection of MR409 significantly reduced deposition of calcium on aorta,as detected by Micro-CT and Alirazin Red staining..ConclusionsGHRH-A can inhibits calcification on SMCs through suppressing ROS production and activation of Runx2 and alkline phosphotase via cAMP/PKA pathway...