Hippo Deficiency Leads to Cardiac Dysfunction with Cardiomyocyte De-differentiation

The Hippo pathway regulates organ size by modulating cell proliferation and apoptosis. It is activated by myocardial stress and contributes to myocardial injury by promoting cardiomyocyte apoptosis. We investigated the role of the endogenous Hippo pathway in the stressed heart, using cardiac-specific WW45 knockout mice (WW45 cKO). Unexpectedly, chronic suppression of the Hippo pathway exacerbated the progression of heart failure induced by pressure overload (PO), despite reducing apoptosis and promoting cardiomyocyte proliferation. WW45 downregulation induced upregulation of YAP and TEF-1 target genes, including oncostatin M (OSM), and fetal-type genes involved in de-differentiation, as well as myofibrillar disorganization and dysfunction in cardiomyocytes. OSM upregulation further upregulated YAP/TEF-1, thereby potentiating de-differentiation. Suppression of any component of the amplification loop, namely YAP, TEF-1, or OSM, inhibited the effect of Hippo downregulation. Thus, cardiomyocytes under stress risk apoptotic death by activating the Hippo pathway in order to maintain differentiation and contraction against hemodynamic overload. Cardiac mRNA profiles of 3-months old control (flox/flox) and cardiac specific WW45 knockout (flox/flox-alpha-MHC-CRE) mice were generated. 1 CT and 1 WW45 cKO mice were at baseline conditions, whereas 1 CT and 1 WW45 cKO were subjected to 4 weeks of transverse aortic constriction (TAC).Hippo通路（Hippo pathway）通过调控细胞增殖与凋亡进程调控器官大小。该通路可被心肌应激激活，并通过促进心肌细胞凋亡参与心肌损伤过程。本研究采用心脏特异性WW45敲除小鼠（WW45 cKO），探究了内源性Hippo通路在应激心脏中的作用。出乎意料的是，尽管慢性抑制Hippo通路可减少细胞凋亡并促进心肌细胞增殖，却加重了压力超负荷（pressure overload, PO）诱导的心力衰竭进展。WW45下调可诱导YAP与TEF-1靶基因（包括抑瘤素M（oncostatin M, OSM））以及参与细胞去分化的胎儿型基因的表达上调，同时引发心肌细胞肌原纤维紊乱与功能异常。OSM的上调可进一步增强YAP/TEF-1的表达水平，从而强化细胞去分化过程。抑制该扩增环路中的任一组分（YAP、TEF-1或OSM），均可抵消Hippo通路下调所产生的效应。综上，应激状态下的心肌细胞可通过激活Hippo通路以维持细胞分化状态与收缩功能，抵御血流动力学超负荷，否则将面临凋亡性死亡的风险。本研究生成了3月龄对照（"flox/flox"）与心脏特异性WW45敲除（"flox/flox-α-MHC-CRE"）小鼠的心脏mRNA转录组图谱。其中，1只对照小鼠与1只WW45 cKO小鼠处于基线状态，另有1只对照小鼠与1只WW45 cKO小鼠接受了为期4周的主动脉弓缩窄（transverse aortic constriction, TAC）造模处理。