Enhanced IGF-IIRα Expression Exacerbates Lipopolysaccharide-Induced Cardiac Inflammation, Hypertrophy, and Apoptosis Through Calcineurin Activation

• Published in: Environmental toxicology Vol. 39; no. 11; pp. 5173 - 5186
• Main Authors: Boonha, Khwanchit, Kuo, Wei-Wen, Tsai, Bruce Chi-Kang, Hsieh, Dennis Jine-Yuan, Lin, Kuan-Ho, Lu, Shang-Yeh, Kuo, Chia-Hua, Yang, Liang-Yo, Huang, Chih-Yang
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2024
• Subjects: Actin; Animals; Apoptosis; Apoptosis - drug effects; Calcineurin; Calcineurin - metabolism; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiovascular diseases; Cell Line; Cell survival; Cell Survival - drug effects; Coronary artery disease; Damage; Filaments; Growth factors; Heart diseases; Hypertrophy; Inflammation; Inflammation - chemically induced; Inflammation - metabolism; Insulin; Lipopolysaccharides; Lipopolysaccharides - toxicity; Molecular interactions; Myoblasts; Myoblasts, Cardiac - drug effects; Myoblasts, Cardiac - metabolism; Rats; Receptor, IGF Type 2 - genetics; Receptor, IGF Type 2 - metabolism; Sepsis; Survival; IGF‐IIRα; calcineurin; lipopolysaccharide; heart; cardiovascular disorders
• ISSN: 1520-4081; 1522-7278; 1522-7278
• DOI: 10.1002/tox.24385

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function.