Dataset Information

RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis.

ABSTRACT: The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis).

SUBMITTER: Lauriol J

PROVIDER: S-EPMC4300109 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis.

Lauriol Jessica J Keith Kimberly K Jaffré Fabrice F Couvillon Anthony A Saci Abdel A Goonasekera Sanjeewa A SA McCarthy Jason R JR Kessinger Chase W CW Wang Jianxun J Ke Qingen Q Kang Peter M PM Molkentin Jeffery D JD Carpenter Christopher C Kontaridis Maria I MI

Science signaling 20141021 348

The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specif ...[more]

PMID: 25336613

Similar Datasets

Project description:BACKGROUND:Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. METHODS:We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments. RESULTS:ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-? signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. CONCLUSIONS:Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-? signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling.

Dataset Information

RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis.

Publications

RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets