Youming Chen1, Lan Wang2, Shixing Huang3, Jiangfeng Ke4, Qing Wang5, Zhiwen Zhou6, Wei Chang7. 1. Department of Cardiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China. 2. Department of Radiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. Department of Cardiovascular Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 4. Department of Endocrinology and metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China. 5. Department of Traditional Chinese Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China. 6. Department of Cardiology, Shanghai Xuhui District Central Hospital & Zhongshan-xuhui Hospital, Shanghai, China. Electronic address: zhouzhiwenufo@sina.com. 7. Department of Emergency, Shanghai Xuhui District Central Hospital & Zhongshan-xuhui Hospital, Shanghai, China. Electronic address: changwei1st@163.com.
Abstract
RATIONALE: Oxidative stress plays a critical role in the development of cardiac remodeling and heart failure. Lutein, the predominant nonvitamin A carotenoid, has been shown to have profound effects on oxidative stress. However, the effect of lutein on angiotensin II (Ang II)-induced cardiac remodeling and heart failure remains unknown. OBJECTIVE: The aim of this study was to determine whether lutein is involved in cardiac remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: In vitro experiments with isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) revealed that lutein significantly attenuated Ang II-induced collagen expression in CFs, and cardiomyocyte hypertrophy. The Ang II-induced increases in superoxide generation, inflammation and apoptosis in cultured CFs were strikingly prevented by lutein. In vivo, fibrosis, hypertrophic cardiomyocyte and superoxide generation were analyzed, and lutein was demonstrated to confer resistance to Ang II-induced cardiac remodeling in mice. Mechanistically, RNA sequencing revealed that interleukin-11 (IL-11) expression was significantly upregulated in mouse hearts in response to Ang II infusion and was significantly suppressed in the hearts of lutein-treated mice. Furthermore, IL-11 overexpression blocked the effects of lutein on fibrosis and oxidative stress in CFs and impaired the protective effect of lutein on cardiac remodeling. Notably, we discovered that lutein could reduce Ang II-induced IL-11 expression, at least partly through the regulation of activator protein (AP)-1 expression and activity. CONCLUSIONS: Lutein has potential as a treatment for cardiac remodeling and heart failure via the suppression of IL-11 expression.
RATIONALE: Oxidative stress plays a critical role in the development of cardiac remodeling and heart failure. Lutein, the predominant nonvitamin A carotenoid, has been shown to have profound effects on oxidative stress. However, the effect of lutein on angiotensin II (Ang II)-induced cardiac remodeling and heart failure remains unknown. OBJECTIVE: The aim of this study was to determine whether lutein is involved in cardiac remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS: In vitro experiments with isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) revealed that lutein significantly attenuated Ang II-induced collagen expression in CFs, and cardiomyocyte hypertrophy. The Ang II-induced increases in superoxide generation, inflammation and apoptosis in cultured CFs were strikingly prevented by lutein. In vivo, fibrosis, hypertrophic cardiomyocyte and superoxide generation were analyzed, and lutein was demonstrated to confer resistance to Ang II-induced cardiac remodeling in mice. Mechanistically, RNA sequencing revealed that interleukin-11 (IL-11) expression was significantly upregulated in mouse hearts in response to Ang II infusion and was significantly suppressed in the hearts of lutein-treated mice. Furthermore, IL-11 overexpression blocked the effects of lutein on fibrosis and oxidative stress in CFs and impaired the protective effect of lutein on cardiac remodeling. Notably, we discovered that lutein could reduce Ang II-induced IL-11 expression, at least partly through the regulation of activator protein (AP)-1 expression and activity. CONCLUSIONS:Lutein has potential as a treatment for cardiac remodeling and heart failure via the suppression of IL-11 expression.