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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Hexarelin suppresses cardiac fibroblast proliferation and collagen synthesis in rat
Xiangbin Xu1, Jinjiang Pang, Hongchao Yin
1Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medical Sciences, Peking Union Medical College, Beijing 100005, People's Republic of China.
Insights
Hexarelin, a growth hormone secretagogue, inhibits cardiac fibroblast proliferation and collagen synthesis. This effect is mediated by activating growth hormone secretagogue receptors (GHSR) and adenosine A2 receptors (A2R), reducing TGF-beta.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Pharmacology
Background:
- Cardiac fibroblast proliferation is central to cardiac hypertrophy and remodeling.
- Hexarelin, a synthetic growth hormone secretagogue (GHS), shows cardiovascular protective effects.
- Mechanisms of GHS action on cardiac fibrosis remain unclear.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms of hexarelin's effect on cardiac fibroblasts.
- To investigate hexarelin's impact on fibroblast proliferation, DNA synthesis, and collagen production.
- To determine the role of growth hormone secretagogue receptor (GHSR) and adenosine receptors in hexarelin's action.
Main Methods:
- Cultured rat cardiac fibroblasts were stimulated with angiotensin II (ANG II) or fetal calf serum (FCS).
- Proliferation and collagen synthesis assessed via MTT assay, (3)H-thymidine, and (3)H-proline incorporation.
- Transforming growth factor-beta (TGF-beta) mRNA and active TGF-beta1 levels measured by RT-PCR and ELISA; cellular cAMP by radioimmunoassay. Adenosine receptor antagonists (DMPX, DPCPX) were used.
Main Results:
- Hexarelin inhibited ANG II-induced proliferation and collagen synthesis.
- Hexarelin reduced FCS- and TGF-beta-induced DNA synthesis and ANG II-induced TGF-beta mRNA upregulation and TGF-beta1 release.
- Hexarelin increased cellular cAMP levels; its effects were abolished by the adenosine A(2)R antagonist DMPX, but not the A(1)R antagonist DPCPX.
Conclusions:
- Hexarelin inhibits cardiac fibroblast proliferation, DNA, and collagen synthesis.
- These effects are mediated through activation of both GHSR and adenosine A(2)R.
- Hexarelin diminishes ANG II-induced increases in TGF-beta expression and release, contributing to its cardioprotective role.
Abstract:
Abnormal growth of cardiac fibroblasts is critically involved in the pathophysiology of cardiac hypertrophy/remodeling. Hexarelin is a synthetic growth hormone secretagogue (GHS), which possesses a variety of cardiovascular protective activities mediated via the GHS receptor (GHSR), including improving cardiac dysfunction and remodeling. The cellular and molecular mechanisms underlying the effect of GHS on cardiac fibrosis are, however, not clear. In this report, cultured cardiac fibroblasts from 8-day-old rats were stimulated with ANG II or FCS to induce proliferation. The fibroblast proliferation and DNA and collagen synthesis were evaluated utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, (3)H-thymidine incorporation, and (3)H-proline incorporation. The level of mRNA of transforming growth factor (TGF)-beta was evaluated by RT-PCR, and the active TGF-beta1 release from cardiac fibroblasts was evaluated by ELISA. The level of cellular cAMP was measured by radioimmunoassay. In addition, the effects of 3,7-dimethyl-l-propargylxanthine (DMPX; a specific adenosine receptor A(2)R antagonist) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a specific A(1)R antagonist) were tested. It was found that incubation with 10(-7) mol/l hexarelin for 24 h 1) inhibited the ANG II-induced proliferation and collagen synthesis and the 5% FCS- and TGF-beta-induced increase of DNA synthesis in cardiac fibroblast and 2) reduced ANG II-induced upregulation of TGF-beta mRNA expression and active TGF-beta1 release from fibroblasts. Hexarelin increased the cellular level of cAMP in cardiac fibroblasts. DMPX (10(-8) mol/l) but not DPCPX abolished the effect of hexarelin on cardiac fibroblast DNA synthesis. It is concluded that hexarelin inhibits DNA and collagen synthesis and proliferation of cardiac fibroblasts through activation of both GHSR and A(2)R and diminishment of ANG II-induced increase in TGF-beta expression and release.
