Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility

Adams, Volker; Linke, Axel; Wisløff, Ulrik; Döring, Christian; Erbs, Sandra; Kränkel, Nicolle; Witt, Christian; Labeit, Siegfried; Müller‐Werdan, Ursula; Schuler, Gerhard; Hambrecht, Rainer

doi:10.1016/j.cardiores.2006.10.026

Cited by 86 publications

(89 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is readily understood that infarct inflammation may result from myocardial damage and healing stress, which involve immune cell infiltration 23, 24, 25. However, it is noteworthy here that the remote area remains in the inflammatory state after MI, which can be observed even after 7 weeks 26. The present study observed remote inflammation at 4 weeks.…”

Section: Discussionmentioning

confidence: 38%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

140

108

View full text Add to dashboard Cite

It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

show abstract

Section: Discussionmentioning

confidence: 38%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

140

108

View full text Add to dashboard Cite

show abstract

“…22,23,39,40 Our results showed unaltered TnI expression in our Pak1 cKO /TAC hypertrophic model, whereas other studies have reported a reduction in TnI expression in chronic heart failure or ischemia/reperfusion models. 23,39 The difference observed is likely due to the dissimilar stress challenges. Usui et al 40 observed exacerbated I-kB expression in the absence of Fbxo32; however, I-kB expression was unchanged in our Pak1 cKO /TAC-model ( Figure S8).…”

Section: Discussionmentioning

confidence: 38%

“…In addition, we examined desmin and troponin I (TnI), targets of Fbxo32. 22,23 Desmin but not TnI expression increased in Pak1 cKO /TAC mice ( Figure S3). To elucidate the link between Pak1-mediated Fbxo32 upregulation and resultant PP2B downregulation, a NRCM cellular model was used.…”

Section: Pak1 Negatively Regulates Pp2b Through Fbxo32 In Response Tomentioning

confidence: 99%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

View full text Add to dashboard Cite

Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC -286 -binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

show abstract

“…Recent studies have demonstrated induction of atrogin-1 in other dying or involuting tissues. For example, it is induced in cardiac muscle in failing hearts (24,25), in uterine smooth muscle in the postpartum period as the uterus involutes to its resting size (26), and in dying stromal tumors responding to imatinib treatment (27). We reasoned that since atrogin-1 plays a key role in activating protein breakdown in a wide range of tissues, especially skeletal muscle, it might also mediate part of their sensitivity to statins.…”

Section: Introductionmentioning

confidence: 99%

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Hanai¹,

Cao²,

Tanksale³

et al. 2007

J. Clin. Invest.

178

218

View full text Add to dashboard Cite

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.

show abstract

Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility

Abstract: TNF-alpha, which is increasingly expressed in CHF, induces troponin I degradation through a MAFbx/Murf-1-dependent pathway. This was associated with an impairment of contractility and might be one mechanism involved in the adverse remodeling process in CHF.

Cited by 86 publications

References 46 publications

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Contact Info

Product

Resources

About