TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice

Dou, Zhen; Gaussin, Vinciane; Taffet, George E.; Belaguli, Narasimhaswamy S.; Yamada, M.; Schwartz, Robert J.; Michael, Lloyd H.; Overbeek, Paul A.; Schneider, Michael

doi:10.1038/75037

Cited by 318 publications

(258 citation statements)

References 41 publications

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“…LKB1 is a tumor suppressor in Peutz-Jeghers syndrome and other cancers (10,24), and AMPK activity is a suppressor of cardiac hypertrophy (34,35), indicating a plausible role for TAK1 in cell growth control. Cardiac hypertrophy results from both inhibition and excess of TAK1 activity (18), albeit associated with volume overload and fulminant apoptosis, respectively, as potential instigators: whether TAK1 directly participates in cardiac myocyte growth is presently unproven. Because LKB1 is not thought to be activated by ischemia yet is required in the heart for AMPK␣2 activation (36), it will be important to ascertain whether TAK1 is required for assembly or trafficking of the LKB1 signaling module (25) or perhaps regulation of substrate readiness, and whether TAK1 is essential for the Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Neonatal rat cardiomyocytes were cultured as described (18). Mouse embryo fibroblasts were isolated at embryonic day 12.5.…”

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confidence: 99%

“…Western blots and real-time quantitative RT-PCR were performed as described (18). For antibody sources, see Supporting Text.…”

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confidence: 99%

“…TAK1 immunoprecipitates were assayed using His-MKK6 as substrate (18,41). AMPK (42) and LKB1 (42,43) were assayed as described.…”

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confidence: 99%

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A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

Xie¹,

Zhang²,

Dyck

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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TGF-␤-activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMPactivated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1͞AMPK signaling axis, an essential governor of cell metabolism. APKs, MAPKKs (MAP2Ks), and MAP2K kinases (MAP3Ks) comprise a multitiered signaling cascade that couples extracellular cues and intracellular stresses to diverse effector pathways controlling cell growth, survival, transcription, and function (1). Among upstream members of this superfamily, TGF-␤-activated kinase-1 (TAK1)͞MA PKK kinase-7 (MAP3K7) first was identified as a mammalian kinase that complements the lack of Ste11, a MAP3K, in yeast and is activated by TGF-␤ and the relative, bone morphogenetic protein (2). Within the MAPK family, TAK1 is coupled preferentially to JNK and p38. Additional inputs for TAK1 activation include cytokine signaling and innate immunity, and additional outputs include I B kinase ␤ (3). Disruption of TAK1 by saturation mutagenesis in ES cells substantiated that TAK1 is indeed essential for a subset of TGF-␤ effects and also exerts essential functions in signaling by cytokine and Toll-like receptors (3), as proposed on earlier grounds. Additionally, the early-lethal phenotype of TAK1-null embryos, with intraembryonic and yolk sac vascular patterning defects, resembles that of mice devoid of other TGF-␤ signaling proteins, the type I receptor Alk1 and type III receptor endoglin (4).A recognized limitation of germ-line deletions is that potential gene functions may be obscured by early lethality, indirect effects, or secondary adaptations, fueling interest in lineagerestr...

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Section: Discussionmentioning

confidence: 99%

“…Neonatal rat cardiomyocytes were cultured as described (18). Mouse embryo fibroblasts were isolated at embryonic day 12.5.…”

mentioning

confidence: 99%

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A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway

Xie¹,

Zhang²,

Dyck

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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322

244

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“…In contrast, the structurally divergent Smad6 and Smad7 inhibit TGF-β signaling (inhibitory Smads). Recently, it has become increasingly apparent that TGF-β not only activates Smads, but also signals through Smad-independent pathways [321] that may involve c-Abl [322], p21-activated kinase-2 (PAK2) [323], TGF-β Activated Kinase (TAK)-1 [324], and p38 MAPK [325].…”

Section: Tgf-β Signaling Pathways In Cardiac Injurymentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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