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

5 Citations (Scopus)

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

Fingerprint

Vascular Calcification
Growth Hormone-Releasing Hormone
Alkaline Phosphatase
Cyclic AMP-Dependent Protein Kinases
Osteogenesis
Smooth Muscle Myocytes
Small Interfering RNA
Aorta
Reactive Oxygen Species
Osteonectin
Hormone Antagonists
Osteoprotegerin
Osteocalcin
Subcutaneous Injections
Cytoplasmic and Nuclear Receptors
Parathyroid Hormone
NADP
Genes
Young Adult
Oxidoreductases

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Shen, J., Zhang, N., Lin, Y. N., Xiang, P. P., Liu, X. B., Shan, P. F., ... 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

Regulation of vascular calcification by growth hormone-releasing hormone and its agonists. / Shen, Jian; Zhang, Ning; Lin, Yi Nuo; Xiang, Ping Ping; Liu, Xian Bao; Shan, Peng Fei; Hu, Xin Yang; Zhu, Wei; Tang, Yao Liang; Webster, Keith A.; Cai, Renzhi; Schally, Andrew V.; Wang, Jian'an; Yu, Hong.

In: Circulation research, Vol. 122, No. 10, 05.2018, p. 1395-1408.

Research output: Contribution to journalArticle

Shen, J, Zhang, N, Lin, YN, Xiang, PP, Liu, XB, Shan, PF, Hu, XY, Zhu, W, Tang, YL, Webster, KA, Cai, R, Schally, AV, Wang, J & Yu, H 2018, 'Regulation of vascular calcification by growth hormone-releasing hormone and its agonists', Circulation research, vol. 122, no. 10, pp. 1395-1408. https://doi.org/10.1161/CIRCRESAHA.117.312418
Shen, Jian ; Zhang, Ning ; Lin, Yi Nuo ; Xiang, Ping Ping ; Liu, Xian Bao ; Shan, Peng Fei ; Hu, Xin Yang ; Zhu, Wei ; Tang, Yao Liang ; Webster, Keith A. ; Cai, Renzhi ; Schally, Andrew V. ; Wang, Jian'an ; Yu, Hong. / Regulation of vascular calcification by growth hormone-releasing hormone and its agonists. In: Circulation research. 2018 ; Vol. 122, No. 10. pp. 1395-1408.
@article{08f16827eebb44de9871c4898da24782,
title = "Regulation of vascular calcification by growth hormone-releasing hormone and its agonists",
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.",
keywords = "Alkaline phosphatase, Growth hormone-releasing hormone, Myocytes, Osteogenesis, Reactive oxygen species, Smooth muscle",
author = "Jian Shen and Ning Zhang and Lin, {Yi Nuo} and Xiang, {Ping Ping} and Liu, {Xian Bao} and Shan, {Peng Fei} and Hu, {Xin Yang} and Wei Zhu and Tang, {Yao Liang} and Webster, {Keith A.} and Renzhi Cai and Schally, {Andrew V.} and Jian'an Wang and Hong Yu",
year = "2018",
month = "5",
doi = "10.1161/CIRCRESAHA.117.312418",
language = "English (US)",
volume = "122",
pages = "1395--1408",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Regulation of vascular calcification by growth hormone-releasing hormone and its agonists

AU - Shen, Jian

AU - Zhang, Ning

AU - Lin, Yi Nuo

AU - Xiang, Ping Ping

AU - Liu, Xian Bao

AU - Shan, Peng Fei

AU - Hu, Xin Yang

AU - Zhu, Wei

AU - Tang, Yao Liang

AU - Webster, Keith A.

AU - Cai, Renzhi

AU - Schally, Andrew V.

AU - Wang, Jian'an

AU - Yu, Hong

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - Alkaline phosphatase

KW - Growth hormone-releasing hormone

KW - Myocytes

KW - Osteogenesis

KW - Reactive oxygen species

KW - Smooth muscle

UR - http://www.scopus.com/inward/record.url?scp=85056787827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056787827&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.117.312418

DO - 10.1161/CIRCRESAHA.117.312418

M3 - Article

C2 - 29618597

AN - SCOPUS:85056787827

VL - 122

SP - 1395

EP - 1408

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 10

ER -