Tollip attenuated the hypertrophic response of cardiomyocytes induced by IL-1beta

Hu, Yulong; Li, Ting; Wang, Yongmei; Li, Jing; Guo, Lin; Wu, Meiling; Shan, Xiaohong; Que, Lingli; Ha, Tuanzhu; Qi, Chen; Kelley, Jim; Li, Yuehua

doi:10.2741/3411

Cited by 14 publications

(10 citation statements)

References 25 publications

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“… 46 It is also reported that IL‐1β can induce hypertrophic response in cardiomyocytes. 47 In addition, our data show that fatVHL1Ako mice have the highest serum levels of the biologically active IL‐12p70, suggesting a potentially important role of IL‐12p70 in exacerbating the pathological conditions induced by adipocyte HIF activation. It is, however, worth noting that, although being associated with inflammatory heart diseases, 48 elevated serum levels of IL‐6, IFNγγ, and TNFα are not critically involved in the development of fatal cardiac hypertrophy and dysfunction in fatVHL1Ako mice.…”

Section: Discussionmentioning

confidence: 64%

Activation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy

Lin

Huang

Booth

et al. 2013

JAHA

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BackgroundObesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia‐signaling pathway plays an essential role in the development of obesity‐associated cardiomyopathy.Methods and ResultsUsing a mouse model in which the hypoxia‐inducible factor (HIF) pathway is activated by deletion of the von Hippel–Lindau gene specifically in adipocytes, we found that mice with adipocyte–von Hippel–Lindau deletion developed lethal cardiac hypertrophy. HIF activation in adipocytes results in overexpression of key cardiomyopathy‐associated genes in adipose tissue, increased serum levels of several proinflammatory cytokines including interleukin‐1β and monocyte chemotactic protein‐1, and activation of nuclear factor–κB and nuclear factor of activated T cells in the heart. Interestingly, genetic deletion of Hif2a, but not Hif1a, was able to rescue cardiac hypertrophy and abrogate adipose inflammation.ConclusionWe have discovered a previously uncharacterized mechanism underlying a critical and direct role of the adipocyte HIF‐2 transcription factor in the development of adipose inflammation and pathological cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 64%

Activation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy

Lin

Huang

Booth

et al. 2013

JAHA

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“…This molecule is ubiquitously expressed, with particularly high expression levels in the heart (Liu et al ., ). Studies from our group and others recently reported that Tollip negatively regulates pathological cardiac hypertrophy in vivo and in vitro (Hu et al ., ; Liu et al ., ), suggesting a critical role for Tollip in heart disease. However, despite pressure overload and myocardial ischaemia being major contributors to heart failure, distinct pathological processes participate in cardiac hypertrophy and MI (Heineke and Molkentin, ; Heusch et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Toll‐interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis

Wan

Liu

Zhang

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEToll-interacting protein (Tollip) is an endogenous inhibitor of toll-like receptors, a superfamily that plays a pivotal role in various pathological conditions, including myocardial infarction (MI). However, the exact role of Tollip in MI remains unknown. EXPERIMENTAL APPROACHMI models were established in Tollip knockout (KO) mice, mice with cardiac-specific overexpression of human Tollip gene and in their Tollip +/+ and non-transgenic controls respectively. The effects of Tollip on MI were evaluated by mortality, infarct size and cardiac function. Hypoxia-induced cardiomyocyte damage was investigated in vitro to confirm the role of Tollip in heart damage. KEY RESULTSTollip expression was dramatically up-regulated in human ischaemic hearts and infarcted mice hearts. MI-induced mortality, infarct size and cardiac dysfunction were decreased in Tollip-KO mice compared with Tollip +/+ controls. Ischaemic hearts from Tollip-KO mice exhibited decreased inflammatory cell infiltration and reduced NF-κB activation. Tollip depletion also alleviated myocardial apoptosis by down-regulating pro-apoptotic protein levels and up-regulating anti-apoptotic protein expressions in infarct border zone. Conversely, MI effects were exacerbated in mice with cardiac-specific Tollip overexpression. This aggravated MI injury by Tollip in vivo was confirmed with in vitro assays. Inhibition of Akt signalling was associated with the detrimental effects of Tollip on MI injury; activation of Akt largely reversed the deleterious effects of Tollip on MI-induced cardiomyocyte death. CONCLUSIONS AND IMPLICATIONSTollip promotes inflammatory and apoptotic responses after MI, leading to increased mortality and aggravated cardiac dysfunction. These findings suggest that Tollip may serve as a novel therapeutic target for the treatment of MI.

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“…The anti-inflammatory properties of TMP have been reported to involve the suppression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (8). These cytokines have been implicated in the pathogenesis of cardiac hypertrophy (10,11). However, the effects of TMP on cardiac hypertrophy and the expression of TNF-α in cardiomyocytes remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine inhibits angiotensin II-induced cardiomyocyte hypertrophy and tumor necrosis factor-α secretion through an NF-κB-dependent mechanism

She

et al. 2013

International Journal of Molecular Medicine

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Tetramethylpyrazine (TMP), a bioactive compound isolated from the Chinese herb, Ligusticum wallichii Franchat, has been reported to play a protective role in cardiac diseases. However, the cellular and molecular mechanisms behind the protective effects of TMP on the heart remain to be elucidated. In this study, we aimed to determine the effects of TMP on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and its possible mechanisms of action. In addition, we investigated whether TMP regulates tumor necrosis factor-α (TNF-α) secretion and expression. We found that TMP significantly inhibited the Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by the decrease in [3H]leucine incorporation and β-myosin heavy chain (β-MHC) mRNA expression. TMP inhibited Ang II-stimulated TNF-α protein secretion and mRNA expression in the cardiomyocytes. Further experiments revealed that Ang II increased the level of the phosphorylated form of the transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), as well as NF-κB-DNA binding activity in the cardiomyocytes; treatment with TMP significantly inhibited the Ang II-induced activation of NF-κB. Furthermore, the inhibition of NF-κB by the specific inhibitor, pyrrolidine dithiocarbamate (PDTC), markedly attenuated the Ang II-induced increase in [3H]leucine incorporation, β-MHC mRNA expression and TNF-α protein secretion. Our findings suggest that TMP inhibits Ang II-induced cardiomyocyte hypertrophy and TNF-α production through the suppression of the NF-κB pathway, which may provide new insight into the mechanisms underlying the protective effects of TMP in heart diseases.

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Tollip attenuated the hypertrophic response of cardiomyocytes induced by IL-1beta

Cited by 14 publications

References 25 publications

Activation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy

Activation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy

Toll‐interacting protein contributes to mortality following myocardial infarction through promoting inflammation and apoptosis

Tetramethylpyrazine inhibits angiotensin II-induced cardiomyocyte hypertrophy and tumor necrosis factor-α secretion through an NF-κB-dependent mechanism

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