Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways. (October 2021)

• Record Type: Journal Article
• Authors: Huang, Kevin W.; Wang, Ian H.; Fu, Ping; Krum, Henry; Bach, Leon A.; Wang, Bing H.
• Is Part Of: IJC heart & vasculature. Volume 36(2021)
• Publication Date: 2021-10
• Subjects: Insulin-like growth factor 1 -- Rho Associated Protein Kinase -- Apoptosis Signal-regulating Kinase 1 -- p38 MAPK -- Cardiac cellular remodelling; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Pathophysiology -- Periodicals; 616.1005
• DOI: 10.1016/j.ijcha.2021.100852
• Languages: English
• ISSNs: 2352-9067

Abstract

Abstract: Background: Studies of insulin-like growth factor 1 (IGF-1) as a novel therapy for the treatment of cardiovascular diseases have proven promising. However, elevated IGF-1 levels have also been associated with poor patient outcomes in heart failure with reduced ejection fraction. IGF-1 therapy has additionally been shown to not be beneficial in the percutaneous coronary intervention setting. Although IGF-1 activation of the PI3K/Akt and ERK1/2 pathways have been demonstrated as cardioprotective, other cellular mechanisms have not been fully investigated. Methods: Neonatal rat cardiac myocytes (NCMs) and fibroblasts (NCFs) were isolated from 1 to 2-day old pups using enzymatic digestion. NCMs and NCFs were pre-treated with IGF binding protein 6, inhibitors for the PI3K/Akt Wortmannin, ERK1/2 U0126, Rho Associated Protein Kinase (ROCK) GSK576371, Apoptosis Signal-regulating Kinase-1 (ASK-1) G2261818A, and p38MAPK RWJ67657 pathways before stimulation with IGF-1 for 62 and 50 h, respectively. Cardiac myocyte hypertrophy and fibroblast collagen synthesis were determined by 3 H-leucine and 3 H-proline incorporation, respectively. Results: IGF-1 dose-dependently stimulated NCM hypertrophy and NCF collagen synthesis. Treatment with IGFBP6 and the kinase inhibitors, Wortmannin, U0126, GSK576371, G2261818A and RWJ67657 significantly inhibited IGF-1 stimulated NCM hypertrophy and NCF collagen synthesis. Conclusion: This study is the first to demonstrate that IGF-1 treatment in NCMs and NCFs activates the ROCK, ASK-1 and p38MAPK pathways. Future research may be guided by consideration of the PI3K/Akt and ERK1/2 pathways potentially increasing collagen synthesis, and the utilisation of a biased agonist to reduce activation of the ROCK, ASK-1 and p38MAPK pathways to maximise cardioprotective benefit whilst mitigating risks.