Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury

Pu, Jun; Yuan, Ancai; Shan, Peiren; Gao, Erhe; Wang, Xiaoliang; Wang, Yajing; Lau, Wayne Bond; Koch, Walter J.; He, Ben

doi:10.1093/eurheartj/ehs011

Cited by 174 publications

(167 citation statements)

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“…Autophagy is an important player in cardiovascular disease development such as atherosclerosis, cardiac ischemia/reperfusion (I/R), cardiomyopathy, heart failure, and hypertension. [44][45] However, the pathophysiological role of autophagy in cardiovascular diseases is controversial. Apoptosis invariably contributes to cell death, but autophagy plays dual roles in cell death or survival, which might depend on the cellular context.…”

Section: Discussionmentioning

confidence: 99%

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Song¹,

Wang³

et al. 2015

Autophagy

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(2015) ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation, Autophagy, 11:8, 1308-1325, DOI: 10.1080/15548627.2015 Keywords: ATG16L1, autophagy, cardiomyocyte, casein kinase 2, protein phosphatase 1 Abbreviations: ACTB, actinb; AMPK, AMP activated protein kinase; ATG, autophagy-related; BCL2, B-cell CLL/lymphoma 2; BECN1/Beclin 1, autophagy related; CD, Crohn disease; CSNK2, casein kinase 2; GFP, green fluorescent protein; GNB2L1/ RACK1, guanine nucleotide binding protein (G protein)bpolypeptide 2-like 1; GST, glutathione S-transferase; H/R, hypoxia/reoxygenation; I/R, ischemia/reperfusion; LAD, left anterior descending; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; mRFP, monomeric red fluorescent protein; MTORC1, mechanistic target of rapamycin complex 1; NRVCs, neonatal rat ventricular cardiomyocytes; OA, okadaic acid; PE, phosphatidylethanolamine; PPP1, protein phosphatase 1; PPP2, protein phosphatase 2; PVDF, polyvinylidenedifluoride; SNP, single nucleotide polymorphism; SUPT20H/p38IP, suppressor of Ty 20 homolog (S. cerevisiae); TBB, 4,5,6,7-tetrabromobenzotriazole; lPP, l protein phosphatase.Recent studies have shown that the phosphorylation and dephosphorylation of ULK1 and ATG13 are related to autophagy activity. Although ATG16L1 is absolutely required for autophagy induction by affecting the formation of autophagosomes, the post-translational modification of ATG16L1 remains elusive. Here, we explored the regulatory mechanism and role of ATG16L1 phosphorylation for autophagy induction in cardiomyocytes. We showed that ATG16L1 was a phosphoprotein, because phosphorylation of ATG16L1 was detected in rat cardiomyocytes during hypoxia/ reoxygenation (H/R). We not only demonstrated that CSNK2 (casein kinase 2) phosphorylated ATG16L1, but also identified the highly conserved Ser139 as the critical phosphorylation residue for CSNK2. We further established that ATG16L1 associated with the ATG12-ATG5 complex in a Ser139 phosphorylation-dependent manner. In agreement with this finding, CSNK2 inhibitor disrupted the ATG12-ATG5-ATG16L1 complex. Importantly, phosphorylation of ATG16L1 on Ser139 was responsible for H/R-induced autophagy in cardiomyocytes, which protects cardiomyocytes from apoptosis. Conversely, we determined that wild-type PPP1 (protein phosphatase 1), but not the inactive mutant, associated with ATG16L1 and antagonized CSNK2-mediated phosphorylation of ATG16L1. Interestingly, one RVxF consensus site for PPP1 binding in the C-terminal tail of ATG16L1 was identified; mutation of this site disrupted its association with ATG16L1. Notably, CSNK2 also associated with PPP1, but ATG16L1 depletion impaired the interaction between CSNK2 and PPP1. Collectively, these data identify ATG16L1 as a bona fide physiological CSNK2 and PPP1 substrate, which reveals a novel molecular link from CSNK2 to activation of the autophagy-specific ATG12-ATG5-ATG16L1 complex and autoph...

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Section: Discussionmentioning

confidence: 99%

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Song¹,

Wang³

et al. 2015

Autophagy

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“…All the studies involving human samples were approved by the Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao tong University, and conformed to the principles outlined in the Declaration of Helsinki. An expanded Materials and Methods section is available in the online-only Data Supplement, which includes detailed information on the following aspects: generation of global USP4 knockout and USP4 transgenic mice, surgical procedure of AB, 21 histological analysis, echocardiographic measurement, 22 culture of neonatal rat ventricular myocytes and adenovirus transfection, 23,24 immunofluorescence analysis, 25,26 ubiquitination assay, 27 immunoprecipitation, Western blot and quantitative real-time polymerase chain reaction, and human heart samples.…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Zhao

Gao

et al. 2016

Hypertension

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Abstract-Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain-and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy. promotes ionizing radiation-induced cell apoptosis by specifically reducing p53 expression. 13 Of note, USP4 is a putative proto-oncogene, which promotes epithelial to mesenchymal transition and breast cancer cell migration. 18 Interestingly, mounting evidence supports pivotal roles of proto-oncogenes in modulating cardiac hypertrophy, 19,20 indicating a potential involvement of USP4 in cardiac hypertrophy. We therefore posited that USP4, a DUB prominently expressed in the heart, might be a potential signaling regulator implicated in cardiac hypertrophy.In this study, we observed reduced levels of USP4 in hearts from patients with dilated cardiomyopathy and in animal models of cardiac hypertrophy induced by pressure overload. By subjecting USP4 knockout mice and transgenic mice with cardiac-specific USP4 overexpression to aortic banding (AB), we observed that USP4 deficiency aggravated hypertrophic growth and cardiac dysfunction. Conversely, restoration of USP4 level remarkably protected the heart against pathological hypertrophy. Mechanistically, the beneficial effect of USP4 was largely dependent on the blockade of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling. Materials and MethodsThe animal protocol was approved by the Instit...

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“…Mechanistically, LXRα activation significantly decreases myocardial NADPH oxidase expression, attenuates superoxide generation, and reduces iNOS and tissue nitrotyrosine content in myocardium after ischemia/reperfusion (He et al, 2014a). In addition, several members of the nuclear hormone receptor superfamily, such as PPARs, estrogen receptors and androgen receptors, have been proposed as the endogenous protective receptors that act against myocardial apoptosis and MI/R injury, while the activation of the farnesoid X receptor and Nur77 exacerbates myocardial apoptosis and MI/R injury (Lin et al, 2009;Pu et al, 2013;Tsang et al, 2008). Therefore, it is conceivable that potential regulatory cross-talk among LXRα and these nuclear factors may maintain a delicate homeostatic balance between cellular death and survival in the heart.…”

Section: Role Of Lxrs Against Myocardial Diseases Myocardial Ischemiamentioning

confidence: 99%

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

Ma¹,

Deng²,

Hu³

et al. 2017

Current Issues in Molecular Biology

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Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets.

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Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury

Abstract: These results demonstrate that nuclear receptor FXR acts as a novel functional receptor in cardiac tissue, regulates apoptosis in cardiomyocytes, and contributes to MI/R injury.

Cited by 174 publications

References 17 publications

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

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