Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction. (June 2022)

• Record Type: Journal Article
• Authors: Wang, Yong-Li; Bai, Lan; Shi, Xue-Rui; Zhu, Hong; Du, Lin-Juan; Liu, Yuan; Ma, Xiao-Xin; Lin, Wen-Zhen; Liu, Ting; Sun, Jian-Yong; Liu, Yan; Guo, Xu-Guang; Zhou, Lu-Jun; Chen, Bo-Yan; Shao, Shuai; Meng, Xiao-Qian; Li, Yu-Lin; Li, Ruo-Gu; Duan, Sheng-Zhong
• Is Part Of: Journal of molecular and cellular cardiology. Volume 167(2022)
• Page Start: 40
• Page End: 51
• Publication Date: 2022-06
• Subjects: Ventricular remodeling -- Mineralocorticoid receptor -- Osteoblast -- Osteocalcin -- Macrophage; MR mineralocorticoid receptor -- MI myocardial infarction -- OCN osteocalcin -- ucOCN undercarboxylated OCN -- BrdU bromodeoxyuridine -- LV left ventricular -- EF ejection fraction -- FS fractional shortening; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.03.003
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Rationale: Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood. Methods and results: Using osteoblast MR knockout (MR obko ) mouse in combination with myocardial infarction (MI) model, we demonstrated that MR deficiency in osteoblasts significantly improved cardiac function, promoted myocardial healing, as well as attenuated cardiac hypertrophy, fibrosis and inflammatory response after MI. Gene expression profiling using RNA sequencing revealed suppressed expression of osteocalcin (OCN) in calvaria from MR obko mice compared to littermate control (MR fl/fl ) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MR obko mice compared to MR fl/fl mice. Administration of ucOCN abolished the protective effects of osteoblast MR deficiency on infarcted hearts. Mechanistically, ucOCN treatment promoted proliferation and inflammatory cytokine secretion in macrophages. Spironolactone, an MR antagonist, significantly inhibited the expression and secretion of OCN in post-MI mice. More importantly, spironolactone decreased plasma levels of ucOCN and inflammatory cytokines in heart failure patients. Conclusions: MR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients. Graphical abstract: Unlabelled Image Highlights: Osteoblast MR may be a target for treating pathological ventricular remodeling after MI. Osteoblast MR regulates ventricular remodeling remotely by ucOCN. ucOCN promotes proliferation and inflammation of macrophages. ucOCN is closely correlated with cardiac function in post-MI mice. The cardiac benefit of MR antagonists may be partially mediated by osteoblastic MR.