lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.
lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.
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DOI：
10.1161/circulationaha.121.056850
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发表时间：
2022-04-19
期刊：
影响因子：
37.8
通讯作者：
Rosenzweig, Anthony
中科院分区：
文献类型：
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作者：
Li, Haobo;Trager, Lena E.;Liu, Xiaojun;Hastings, Margaret H.;Xiao, Chunyang;Guerra, Justin;To, Samantha;Li, Guoping;Yeri, Ashish;Rodosthenous, Rodosthenis;Silverman, Michael G.;Das, Saumya;Ambardekar, Amrut V.;Bristow, Michael R.;Gonzalez-Rosa, Juan Manuel;Rosenzweig, Anthony
心脏对病理和生理刺激做出反应而生长。前者往往先于心肌细胞丧失和心力衰竭；后者自相矛盾地保护心脏并增强心肌生成。这些差异背后的机制仍然不完全清楚。虽然长非编码RNA(LncRNAs)在心脏发育和疾病中很重要，但人们对它们在生理性肥大或心肌形成中的作用知之甚少。对8周后的小鼠心脏进行RNA测序，观察运动诱导的生理性肥厚和心肌形成或横断性主动脉缩窄(TAC)2周或8周诱导的病理性肥厚或心力衰竭。用腺相关病毒(AAV)载体在心脏中高表达LncRNA，并用反义锁定核酸(LNA)-GapmeRs抑制其功能。通过启动子分析和结合分析鉴定下游效应子。通过斑马鱼的转基因过表达和Cas9敲门小鼠的心脏特异性缺失，研究了新的下游效应因子Dachsous钙粘蛋白相关2(DCHS2)的功能。我们鉴定了运动调节的心脏lncRNAs，称为lncExACTs。LncExACT1在进化上是保守的，在运动心脏中减少，但在人类和实验性心力衰竭中增加。心脏lncExACT1过表达导致病理性肥厚和心力衰竭，而抑制lncExACT1诱导生理性肥厚和心肌生成，从而保护心脏纤维化和功能障碍。LncExACT1通过DCHS2调节microRNA-222、钙调神经磷酸酶信号和Hippo/YAP1信号。斑马鱼心肌细胞DCHS2过表达导致病理性肥大，损害心脏再生，促进损伤后瘢痕形成。相反，小鼠DCHS2缺失可诱导生理性肥大并促进心肌生成。这些研究证实，lncExACT1-DCHS2是一种调节心肌肥大和心肌生成的新途径。LncExACT1-DCHS2作为心脏在生理和病理生长之间切换的主开关，以确定功能结果，为利用运动的有益效果提供了一个潜在的易于处理的治疗靶点。
The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. While long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis. RNA sequencing was applied to hearts from mice after eight weeks voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction (TAC) for two or eight weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus (AAV) vectors and inhibited with antisense locked nucleic acid (LNA)-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice. We identified exercise-regulated cardiac lncRNAs, termed lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure, while lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis. These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.
影响因子：
9.5
作者：
Park M;Vatner SF;Yan L;Gao S;Yoon S;Lee GJ;Xie LH;Kitsis RN;Vatner DE
通讯作者：
Vatner DE