Regulation of vascular calcification by growth hormone-releasing hormone and its agonists

Jian Shen, Ning Zhang, Yi Nuo Lin, Ping Ping Xiang, Xian Bao Liu, Peng Fei Shan, Xin Yang Hu, Wei Zhu, Yao Liang Tang, Keith A. Webster, Renzhi Cai, Andrew V. Schally, Jian'an Wang, Hong Yu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Rationale: 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. Objective: 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. Methods and Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1395-1408
Number of pages14
JournalCirculation research
Volume122
Issue number10
DOIs
StatePublished - May 2018

Keywords

  • Alkaline phosphatase
  • Growth hormone-releasing hormone
  • Myocytes
  • Osteogenesis
  • Reactive oxygen species
  • Smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Regulation of vascular calcification by growth hormone-releasing hormone and its agonists'. Together they form a unique fingerprint.

  • Cite this

    Shen, J., Zhang, N., Lin, Y. N., Xiang, P. P., Liu, X. B., Shan, P. F., Hu, X. Y., Zhu, W., Tang, Y. L., Webster, K. A., Cai, R., Schally, A. V., Wang, J., & Yu, H. (2018). Regulation of vascular calcification by growth hormone-releasing hormone and its agonists. Circulation research, 122(10), 1395-1408. https://doi.org/10.1161/CIRCRESAHA.117.312418