Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways

Kevin W Huang; Ian H Wang; Ping Fu; Henry Krum; Leon A Bach; Bing H Wang

doi:10.1016/j.ijcha.2021.100852

Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways

Int J Cardiol Heart Vasc. 2021 Aug 2:36:100852. doi: 10.1016/j.ijcha.2021.100852. eCollection 2021 Oct.

Authors

Kevin W Huang^{1

2}, Ian H Wang², Ping Fu³, Henry Krum², Leon A Bach³, Bing H Wang^{1

2}

Affiliations

¹ Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
² Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
³ Central Clinical School, Monash University, Melbourne, Australia.

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 ³H-leucine and ³H-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.

Keywords: Apoptosis Signal-regulating Kinase 1; Cardiac cellular remodelling; Insulin-like growth factor 1; Rho Associated Protein Kinase; p38 MAPK.