LIM and Cysteine-Rich Domains 1 Regulates Cardiac Hypertrophy by Targeting Calcineurin/Nuclear Factor of Activated T Cells Signaling

Abstract

Abstract-LIM domain proteins are important regulators in cell growth, cell fate determination, cell differentiation, and remodeling of the cell cytoskeleton. LIM and cysteine-rich domains 1 (Lmcd1) is a novel protein that contain 2 LIM domains with regular spacing in the carboxy-terminal region. However, its roles in cardiac growth remain unknown. Here, we investigated whether Lmcd1 regulates cardiac hypertrophy in vitro and in vivo and elucidated the underlying molecular mechanisms. We used primary cultured cardiac myocytes and cardiac-specific Lmcd1 transgenic mice. In wild-type mice subjected to the aortic banding, cardiac hypertrophy was evident at 8 weeks. In transgenic mice, however, cardiac hypertrophy was significantly greater than that in wild-type mice, as estimated by heart weight:body weight ratio, cardiomyocyte area, and echocardiographic measurements, as well as cardiac atrial natriuretic peptide and B-type natriuretic peptide mRNA and protein levels. Our results further showed that cardiac fibrosis observed in wild-type aortic banding mice was augmented in transgenic aortic banding mice. Importantly, calcineurin activity and nuclear factor of activated T cells activation level were increased more in transgenic mice than those in wild-type mice after 8-week aortic banding. In vitro experiments in cardiac myocytes further revealed that angiotensin II-induced calcineurin activity and nuclear factor of activated T cells activation were enhanced by overexpression but blunted by downregulation of Lmcd1. In conclusion, our results suggest that Lmcd1 plays a critical role in the development of cardiac hypertrophy via activation of calcineurin/nuclear factor of activated T cells signaling pathway. Key Words: cardiac hypertrophy Ⅲ fibrosis Ⅲ Lmcd1 Ⅲ calcineurin Ⅲ NFAT C ardiac hypertrophy is a response of the myocardium to increased workload, characterized by an increase of myocardial mass and accumulation of extracellular matrix, leading to left ventricular (LV) dilatation, fibrosis, and impaired systolic function, and it potentates the development of ventricular arrhythmias, heart failure, and subsequent cardiovascular mortality. 1,2 Although initially a beneficial adaptive response, prolonged hypertrophy may result in ventricular dilatation and heart failure, which is increasing in prevalence and is a debilitating disease with high rates of mortality and morbidity. [3][4][5][6] However, antihypertensive therapies and aortic valve replacement are the only 2 treatments proven to effectively reverse both structural and functional cardiac abnormalities associated with pathological cardiac hypertrophy. Understanding the underlying processes regulating cardiac remodeling will allow us to identify specific new therapies to improve the long-term outcomes of pathological cardiac hypertrophy in patients.LIM domain proteins are well recognized as key components of the regulatory machinery of the cell and are important regulators in cell growth, cell fate determination, cell differentiation, and remodeling of the ce...

Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

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Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice

“…In an attempt to elucidate the mechanisms underlying the antifibrotic effect of cFLIP, we analyzed key components of TGF-␤1-Smad signaling, which is a crucial pathway in the regulation of fibrosis. 10 Our results demonstrated that cFLIP abrogates Smad 2 phosphorylation and Smad 2/3 translocation in both cultured cardiac fibroblasts and hypertrophied hearts, thus inhibiting collagen synthesis and fibrosis. Recent studies suggest that the TGF-␤1/Smad pathway can be regulated by the MEK-ERK1/2 pathway.…”

LIM and cysteine-rich domains 1 is required for thrombin-induced smooth muscle cell proliferation and promotes atherogenesis

“…Towards exploring the mechanisms of VSMC multiplication during restenosis, we found that thrombin induces the expression of LMCD1 in HASMCs. Previous studies have shown that LMCD1 represses transcriptional factor GATA6 and promotes cardiac hypertrophy (11,12). In line with its role in cardiac hypertrophy, the present findings show that LMCD1 expression is required for thrombin-induced HASMC replication.…”

“…Although the cellular functions of many LIM proteins have been studied (10), there are only a limited number of reports on the biological functions of LMCD1. It was reported that LMCD1 plays a role in the development of cardiac hypertrophy (11). Another study suggests that LMCD1 acts as a transcriptional repressor for GATA6, a zinc-finger transcription factor, in lung and cardiac tissues (12).…”