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Circ Res. 2018 May 11;122(10):1395-1408. doi: 10.1161/CIRCRESAHA.117.312418. Epub 2018 Apr 4.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

Shen J1,2, Zhang N1,2, Lin YN1,2, Xiang P1,2, Liu XB1,2, Shan PF3, Hu XY1,2, Zhu W1,2, Tang YL4, Webster KA5, Cai R5,6,7, Schally AV5,6,7, Wang J1,2, Yu H8,2.

Author information

From the Departments of Cardiology (J.S., N.Z., Y.-N.L., P.P.X., X.-b.L., X.-y.H., W.Z., J.W., H.Y.).
Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China (J.S., N.Z., Y.-N.L., P.P.X., X.-b.L., X.-y.H., W.Z., J.W., H.Y.).
Endocrinology and Metabolism (P.-f.S.).
Vascular Biology Center, Georgia Regents University, Augusta (Y.-l.T.).
Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute (K.A.W., R.C., A.V.S.).
Divisions of Hematology/Oncology, Department of Medicine (R.C., A.V.S.).
Miller School of Medicine, University of Miami, FL; and Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL (R.C., A.V.S.).
From the Departments of Cardiology (J.S., N.Z., Y.-N.L., P.P.X., X.-b.L., X.-y.H., W.Z., J.W., H.Y.)



Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC.


The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model.


Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409.


GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.


alkaline phosphatase; growth hormone-releasing hormone; myocytes, smooth muscle; osteogenesis; reactive oxygen species

[Available on 2019-05-11]

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