Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, University Place, UK (C.S.M., W.H., A.B., K.M., F.V., K.N., C.F., A.R., P.B., E.B.E., C.H., S.M.M., G.L.S., M.W.M., S.A.N., C.M.L.)
Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, University Place, UK (C.S.M., W.H., A.B., K.M., F.V., K.N., C.F., A.R., P.B., E.B.E., C.H., S.M.M., G.L.S., M.W.M., S.A.N., C.M.L.).
Circulation. 2018 Jan 2;137(1):57-70. doi: 10.1161/CIRCULATIONAHA.117.028911. Epub 2017 Oct 13.
Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown.
To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific -deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.
-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum-mediated calcium release, preserving cardiomyocyte contraction after MI.
Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI.
心肌梗死（MI）是全球范围内导致心力衰竭和死亡的主要原因。保持收缩功能和防止心室结构（心脏重构）的不利变化是限制该疾病进展为心力衰竭的关键因素。因此，迫切需要新的治疗靶点来实现这一目标。Runx1 转录因子在 MI 后在成年心肌细胞中的表达增加；然而，Runx1 在心脏中的功能作用尚不清楚。
为了解决这个问题，我们生成了一种新型的他莫昔芬诱导的心肌细胞特异性 -/- 缺陷小鼠。通过冠状动脉结扎使小鼠发生 MI。在全心脏、心肌细胞和分子水平上广泛评估心脏重构和收缩功能。
-/- 缺陷小鼠在 MI 后可防止心脏重构不良，维持心室壁厚度和收缩功能。此外，这些小鼠缺乏偏心性肥大，其心肌细胞的钙处理明显改善。在机制水平上，这些作用是通过蛋白激酶 A 磷酸化磷蛋白和解除肌浆网 Ca-ATP 酶抑制来实现的。Runx1 缺陷小鼠中肌浆网 Ca-ATP 酶活性的增强增加了肌浆网钙含量和肌浆网介导的钙释放，从而在 MI 后维持了心肌细胞的收缩。
我们的数据将 Runx1 确定为一种新的治疗靶点，具有潜在的转化能力，可以对抗不良心脏重构的影响，从而提高 MI 患者的生存率和生活质量。
