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Transforming growth factor ?-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling.

ABSTRACT: Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.Here, we identified an obligate function for TAK1 (transforming growth factor ?-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac-specific ablation of Map3k7 in mice induced spontaneous apoptosis and necroptosis that led to adverse remodeling and heart failure, and these effects were abolished by ablation of tumor necrosis factor receptor-1. Mechanistically, TAK1 functions as a molecular switch in tumor necrosis factor receptor-1 signaling by regulating the formation of 2 cell death complexes, RIP 1 (receptor-interacting protein 1)-FADD (Fas-associated protein with death domain)-caspase 8 and RIP1-RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, inhibition of RIP1 or RIP3 largely blocked necroptotic cell death, adverse remodeling, and heart failure in TAK1-deficient mice.These results indicate that TAK1 functions as a key survival factor in the heart by directly antagonizing necroptosis, which is critical for the maintenance of myocardial homeostasis and the prevention of adverse myocardial remodeling.

SUBMITTER: Li L

PROVIDER: S-EPMC4302054 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling.

Li Lei L Chen Yi Y Doan Jessica J Murray Jason J Molkentin Jeffery D JD Liu Qinghang Q

Circulation 20141002 24

<h4>Background</h4>Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.<h4>Methods and results</h4>Here, we identified an obligate function for TAK1 (transforming growth factor β-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial r ...[more]

PMID: 25278099

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Project description:AimsCardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF.ResultsA positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca2+ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(ω)-nitro-l-arginine methyl ester (l-NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l-NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3-/-) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l-NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.

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Transforming growth factor ?-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling.

Publications

Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling.

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