Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (S.K.K., L.A.B., M.E.M., J.J.M., M.J.A., G.L.M., I.Z.J.).
Department of Sports Science, Seoul National University of Science and Technology, Republic of Korea, Seoul, South Korea (S.K.K.).
Circ Heart Fail. 2021 Feb;14(2):e007279. doi: 10.1161/CIRCHEARTFAILURE.120.007279. Epub 2021 Feb 1.
Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored.
Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry.
Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction.
These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.
醛固酮受体（MR）拮抗剂可降低心力衰竭（HF）的住院率和死亡率，但具体机制尚不清楚。临床前研究表明，MR 在心梗、纤维化和内皮细胞中的抑制作用并不能完全解释其在心脏重构和功能障碍方面的益处。MR 在 HF 中平滑肌细胞（SMCs）中的作用尚未被探索。
雄性小鼠经诱导后可在 SMC 中特异性敲除 MR（SMC-MR-敲除），并与 MR 完整的同窝仔鼠进行对照，通过 27 号横主动脉缩窄术诱导 HF 与假手术对照。4 周后，通过心脏超声、心室内压测量、运动试验、组织学、心脏基因表达和白细胞流式细胞术来测量 HF 表型和机制。
SMC 中 MR 的缺失减轻了横主动脉缩窄诱导的 HF，表现为射血分数、心脏僵硬度、心腔大小、心室内压、肺水肿和运动能力的统计学显著改善。从机制上讲，SMC-MR-敲除可防止心脏重构不良，表现为心肌细胞肥大和胎儿基因表达、间质和血管周围纤维化以及炎症和纤维化基因表达减少。在 MR 完整的对照组小鼠中，压力超负荷导致心脏毛细血管密度和冠状动脉血流储备显著下降。与横主动脉缩窄的 MR 完整同窝仔鼠相比，SMC-MR-敲除小鼠的这些血管参数得到改善。
这些结果提供了一个新的范例，即通过抑制 SMC 中的 MR 阻断 MR，可能有益于 HF，从而改善压力超负荷诱导的肥大时的心脏血液供应，进而减轻导致 HF 进展和症状的不良心脏重构。
