Division of Cardiology, Department of Medicine, Emory University School of Medicine, 3311 WMRB, 323 WMRB, 101 Woodruff Circle, Atlanta, GA, 30322, USA.
Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Sci Rep. 2022 May 25;12(1):8852. doi: 10.1038/s41598-022-12723-2.
Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.
心肌细胞的再生是修复心肌梗死损伤的心脏结构和功能的一种强有力策略。为了推进这一策略，我们发现两种临床批准的药物联合使用（而非单独使用）可以通过心肌细胞增殖使心脏变得更“结实”。具体而言，在成年小鼠的心肌细胞中，美托洛尔（一种心脏选择性β肾上腺素能受体阻滞剂）与三碘甲状腺原氨酸（T3，甲状腺激素）联合使用时，通过抑制核磷酸化 ERK1/2 特异性磷酸酶双特异性磷酸酶-5 的表达，增强了 T3 刺激 ERK1/2 磷酸化和增殖信号的能力。虽然短时间的美托洛尔加 T3 治疗可以在健康小鼠中产生新的心肌，但在心肌梗死后左心室功能障碍和病理性重塑的小鼠中，它可以使心脏变得更“结实”，恢复收缩功能并逆转心室扩张；这些结果是持久的。如果美托洛尔加 T3 的有益效果在人类中得到复制，这种治疗策略有可能彻底解决缺血性心力衰竭。
