Congestive heart failure is a leading cause of death worldwide. It remains an incurable disease process with an estimated two-year mortality rate of 30-50% for patients with the advanced disease. Although we have made great advances in the treatment for heart failure, our understanding of the molecular mechanism leading to heart failure is still limited. My lab has been committed to study the molecular mechanism involved in the transition of a normal heart to failure. In this study, we focus on the investigation of a smal GTPase Rnd3. The biological function of Rnd3 in the heart remains unexplored. One microarray screening study showed a significant decrease in the Rnd3 mRNA levels in failing human myocardium. The goal of this study is to investigate the molecular mechanisms of Rnd3 downregulation in heart failure. In this proposal, we generated Rnd3 knockout mice. We recently reported that the homozygous mice were embryonically lethal with severe hydrocephalus due to the hyperactivation of Notch signaling. The Rnd3 haploinsufficient mice (Rnd3+/-) are fertile and viable without obvious abnormalities under normal physiological conditions. However, following transverse aortic constriction (TAC), the Rnd3+/- mice developed dilated cardiomyopathy (DCM) with heart failure after the pressure overload. Our preliminary data strongly suggest that the patient-relevant Rnd3 haploinsufficient mice are hypersensitive to cardiac stress. The immediate and challenging questions are why and how does the downregulation of Rnd3 result in heart failure? What is the molecular mechanism involved in the transition to cardiac dysfunction? We propose multiple and systemic approaches including in vitro protein-protein interaction analysis, cell culture experiments, and in vivo genetic animal assessments with loss- and gain-of-function strategies to address these questions. The animal models include Rnd3 haploinsufficient mice as well as Rnd3 overexpression transgenic mice. The findings from this proposal should raise clinical implications. We will, for the first time, establish a connection between the downregulation of a genetic factor and the transition of the heart from a normal to a failing state This will provide a potential diagnostic test and additional target for the treatment of the diseas. The study has basic and clinical translational significance for the understanding of human heart failure.
Heart failure is a leading cause of death worldwide. We will study how a gene is up and down regulated during the progress of heart failure, and what is pathological impact of the gene change on the heart failure development. By gaining insight of these mechanisms, we will provide better strategies for heart failure patient treatment.
|Yue, Xiaojing; Lin, Xi; Yang, Tingli et al. (2016) Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1Î±/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1Î± and Regulates Responsive Cardiac Angiogenesis. Hypertension 67:597-605|
|Liu, Baohui; Dong, Huimin; Lin, Xi et al. (2016) RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion. Oncotarget :|
|Jie, Wei; Andrade, Kelsey C; Lin, Xi et al. (2015) Pathophysiological Functions of Rnd3/RhoE. Compr Physiol 6:169-86|
|Liu, Baohui; Lin, Xi; Yang, Xiangsheng et al. (2015) Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity. Cancer Med 4:1404-16|
|Kim, Eun Young; Zhang, Yi; Ye, Bo et al. (2015) Involvement of activated SUMO-2 conjugation in cardiomyopathy. Biochim Biophys Acta 1852:1388-99|
|Yang, Xiangsheng; Wang, Tiannan; Lin, Xi et al. (2015) Genetic deletion of Rnd3/RhoE results in mouse heart calcium leakage through upregulation of protein kinase A signaling. Circ Res 116:e1-e10|
|Surma, Michelle; Handy, Caitlin; Chang, Jiang et al. (2014) ROCK1 deficiency enhances protective effects of antioxidants against apoptosis and cell detachment. PLoS One 9:e90758|
|Yue, X; Yang, X; Lin, X et al. (2014) Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure. Cell Death Dis 5:e1284|
|Wang, Xiaohong; Huang, Wei; Yang, Yang et al. (2014) Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. Biochim Biophys Acta 1842:701-11|
|Wang, Xiaohong; Huang, Wei; Liu, Guansheng et al. (2014) Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J Mol Cell Cardiol 74:139-50|