Leptin-induced Cardiomyocyte Hypertrophy Reveals both Calcium-dependent and Calcium-independent/RhoA-dependent Calcineurin Activation and NFAT Nuclear Translocation

Rajapurohitam, Venkatesh; Izaddoustdar, Farzad; Martínez-Abundis, Eduardo; Karmazyn, Morris

doi:10.1016/j.cellsig.2012.07.025

Cited by 27 publications

(18 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been suggested that calcineurin-NFAT pathway is associated with stimulation of many protein kinase C isoforms and mitogen-activated protein kinase (MAPK) cascades. [8][9][10] KCNE2 is a member of the small auxiliary subunits of voltage-gated cation channels encoded by KCNE family gene.…”

mentioning

confidence: 99%

Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways

Liu

Deng

Ding

et al. 2017

Circ: Heart Failure

View full text Add to dashboard Cite

Background— KCNE2 is a promiscuous auxiliary subunit of voltage-gated cation channels. A recent work demonstrated that KCNE2 regulates L-type Ca 2+ channels. Given the important roles of altered Ca 2+ signaling in structural and functional remodeling in diseased hearts, this study investigated whether KCNE2 participates in the development of pathological hypertrophy. Methods and Results— We found that cardiac KCNE2 expression was significantly decreased in phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes and in transverse aortic constriction–induced cardiac hypertrophy in mice, as well as in dilated cardiomyopathy in human. Knockdown of KCNE2 in neonatal rat ventricular myocytes reproduced hypertrophy by increasing the expression of ANP (atrial natriuretic peptide) and β-MHC (β-myosin heavy chain), and cell surface area, whereas overexpression of KCNE2 attenuated phenylephrine-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased intracellular Ca 2+ transient, calcineurin activity, and nuclear NFAT (nuclear factor of activated T cells) protein levels, and pretreatment with inhibitor of L-type Ca 2+ channel (nifedipine) or calcineurin (FK506) attenuated the activation of calcineurin–NFAT pathway and cardiomyocyte hypertrophy. Meanwhile, the phosphorylation levels of p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were increased, and inhibiting the 3 cascades of mitogen-activated protein kinase reduced cardiomyocyte hypertrophy induced by KCNE2 knockdown. Overexpression of KCNE2 in heart by ultrasound-microbubble–mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin–NFAT and mitogen-activated protein kinase pathways in transverse aortic constriction mice. Conclusions— This study demonstrates that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin–NFAT and mitogen-activated protein kinase pathways. Targeting KCNE2 is a potential therapeutic strategy for the treatment of hypertrophy.

show abstract

mentioning

confidence: 99%

Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways

Liu

Deng

Ding

et al. 2017

Circ: Heart Failure

View full text Add to dashboard Cite

show abstract

“…It was suggested that after calcineurin/NFAT signaling was activated by multiple stimuli, NFAT would be translocated into the cell nucleus to regulate related gene expressions in response to these stimuli [39]. Thus NFAT nuclear translocation is the hallmark event of activation of calcineurin signaling [40]. In this study, NFATc1 nuclear translocation increased in response to high-glucose incubation but attenuated by PERK depletion, indicating that PERK activation was the prior molecular event requited for calcineurin signaling.…”

Section: Discussionmentioning

confidence: 50%

Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy

Liu

Cai

Zhu

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

“…NFATc4 isoform is the prominent isoform in PASMCs 35, 36 . A wide variety of stimuli including ET-1 can raise intracellular Ca 2+ level and activate calcineurin/NFAT signaling pathway 18, 37 . Activation of calcineurin/NFAT signaling pathway has been shown to be associated with the development of PH through induction of PASMCs proliferation and pulmonary vascular remodeling 18, 38 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells

Pan

Rui

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus. Further study indicated that inhibition of calcineurin by cyclosporine A or knockdown of NFATc4 using small interfering RNA suppressed ET-1-induced TRPC6 up-regulation. In addition, luciferase reporter assay showed that NFATc4 directly regulated the expression of TRPC6 in PASMCs. Inhibition of PDE5 by sildenafil suppressed ET-1-induced activation of calcineurin/NFATc4 signaling pathway and consequent TRPC6 up-regulation in PASMCs, while these inhibitory effects of sildenafil were abolished by PKG inhibitor Rp-8Br-cGMPs. Taken together, our study indicates that ET-1 stimulates TRPC6 expression by activation of calcineurin/NFATc4 signaling pathway, and inhibition of PDE5 suppresses calcineurin/NFATc4- mediated TRPC6 expression in PASMCs in a cGMP-PKG-dependent manner.

show abstract

Leptin-induced Cardiomyocyte Hypertrophy Reveals both Calcium-dependent and Calcium-independent/RhoA-dependent Calcineurin Activation and NFAT Nuclear Translocation

Cited by 27 publications

References 45 publications

Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways

Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways

Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy

Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells

Contact Info

Product

Resources

About