Moon Ryan, Vogel Neal T, Mendelson Jenna B, Hartweck Lynn M, Carney John P, Kim Minwoo, Gardner Melissa K, Prisco Sasha, Prins Kurt W
Lillehei Heart Institute, Cardiovascular Division, University of Minnesota, Minneapolis, MN.
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN.
bioRxiv. 2025 Jan 24:2025.01.22.634271. doi: 10.1101/2025.01.22.634271.
The female-predominate sex hormone 17β-estradiol exerts cardioprotective effects via multiple mechanisms. Available data demonstrate 17β-estradiol modulates microtubule dynamics , but its effects on pathogenic microtubule remodeling in pressure-overloaded cardiomyocytes are unexplored. Here, we show 17β-estradiol directly blunts microtubule polymerization , counteracts endothelin-mediated microtubule remodeling in iPSC-cardiomyocytes, and mitigates microtubule stabilization in pulmonary artery banded right ventricular cardiomyocytes. 17β-estradiol treatment blunts cardiomyocyte and nuclear hypertrophy, restores t-tubule architecture, and prevents mislocalization of connexin-43 in RV cardiomyocytes of pulmonary artery banded rats. These cellular phenotypes are paired with significant improvements in RV function. Thus, we propose 17β-estradiol exerts cardioprotective effects via direct modulation of microtubules in addition to its well ascribed signaling functions.
女性占主导的性激素17β-雌二醇通过多种机制发挥心脏保护作用。现有数据表明，17β-雌二醇可调节微管动力学，但其对压力过载心肌细胞中致病性微管重塑的影响尚未得到研究。在此，我们表明，17β-雌二醇直接抑制微管聚合，抵消内皮素介导的诱导多能干细胞衍生心肌细胞中的微管重塑，并减轻肺动脉环扎右心室心肌细胞中的微管稳定。17β-雌二醇治疗可抑制心肌细胞和细胞核肥大，恢复横管结构，并防止肺动脉环扎大鼠右心室心肌细胞中连接蛋白43的定位错误。这些细胞表型与右心室功能的显著改善相关。因此，我们提出，17β-雌二醇除了其已被充分归因的信号功能外，还通过直接调节微管发挥心脏保护作用。
