Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.
Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.
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DOI：
10.1016/j.yjmcc.2022.03.003
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发表时间：
2022-03
影响因子：
5
通讯作者：
Yong-Li Wang;Lan Bai;Xue-Rui Shi;Hong Zhu;Lin-Juan Du;Yuan Liu;Xiao-Xin Ma;Wen-Zhen Lin;Ting Liu;Jian-Yong Sun;Yan Liu;Xu-guang Guo;Lu Zhou;Bo-Yan Chen;S. Shao;X. Meng;Yu-Lin Li;Ruo-Gu Li;S. Duan
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文献类型：
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作者：
Yong-Li Wang;Lan Bai;Xue-Rui Shi;Hong Zhu;Lin-Juan Du;Yuan Liu;Xiao-Xin Ma;Wen-Zhen Lin;Ting Liu;Jian-Yong Sun;Yan Liu;Xu-guang Guo;Lu Zhou;Bo-Yan Chen;S. Shao;X. Meng;Yu-Lin Li;Ruo-Gu Li;S. Duan
盐皮质激素受体（MR）拮抗剂已在临床上用于治疗心力衰竭。然而，潜在的细胞和分子机制仍然不完全understood.Methods and resultsUsing成骨细胞MR基因敲除（MRobko）小鼠与心肌梗死（MI）模型相结合，我们证明，MR缺乏成骨细胞显着改善心脏功能，促进心肌愈合，以及衰减心肌肥厚，纤维化和心肌梗死后的炎症反应。使用RNA测序的基因表达谱显示，与同窝对照（MRFl/fl）小鼠（有或无MI）相比，MRobkomice小鼠颅骨中骨钙素（OCN）的表达受到抑制。与MRFl/flmice小鼠相比，MRobkomice中羧化不足OCN（ucOCN）的血浆水平也显著降低。给药ucOCN可消除成骨细胞MR缺乏对梗死心脏的保护作用。在机制上，ucOCN处理促进巨噬细胞中的增殖和炎性细胞因子分泌。MR拮抗剂螺内酯可显著抑制MI后小鼠OCN的表达和分泌。更重要的是，螺内酯降低血浆水平的ucOCN和炎性细胞因子在heart failure patients.ConclusionsMR缺乏成骨细胞恶化心肌梗死后的病理性心室重构，可能通过其对OCN的调节。螺内酯可能通过成骨细胞MR/OCN轴发挥其对小鼠和人类病理性心室重构和心力衰竭的治疗作用。
RationaleMineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood.Methods and resultsUsing osteoblast MR knockout (MRobko) 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 MRobkomice compared to littermate control (MRfl/fl) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MRobkomice compared to MRfl/flmice. 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.ConclusionsMR 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.