Apoptosis repressor with caspase recruitment domain, a multifunctional modulator of cell death

Ludwig-Gałęzowska, Agnieszka H.; Flanagan, Lorna; Rehm, Markus

doi:10.1111/j.1582-4934.2010.01221.x

Cited by 43 publications

(38 citation statements)

References 60 publications

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“…Regulation of ARC expression during reperfusion is controlled by the expression/ activity of the ubiquitin ligase MDM2. 25,39 MR activation upregulates MDM2, leading to proliferation of vascular smooth muscle cells 45 and, as shown in our studies, degradation of ARC. MDM2 is also the ligase for p53, 46 controlling both ubiquitination and degradation of p53.…”

Section: Discussionsupporting

confidence: 84%

“…38 MR antagonist-induced stabilization of ARC expression prevents activation of the intrinsic pathway at multiple points. ARC inhibits t-Bid generation 39 and caspase 2 processing by the PIDDosome through interaction between the CARD domains of the 2 proteins 40 and prevents Bax activation in response to I-R injury. 17,41 There have been discrepant reports for activation of the death receptor (extrinsic) pathway during I-R, with both the absence of caspase 8 processing noted, 42 confirming our findings, and activation reported by other studies.…”

Section: Discussionmentioning

confidence: 99%

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Low-Dose Spironolactone Prevents Apoptosis Repressor With Caspase Recruitment Domain Degradation During Myocardial Infarction

Mardini

Howell

et al. 2012

Hypertension

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Abstract-Low-dose mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure and myocardial infarction, despite normal plasma aldosterone levels. Since apoptosis plays an important role in heart failure and postinfarction left ventricular remodeling, we examined whether low-dose mineralocorticoid receptor antagonists modulate cardiomyocyte death by regulating the apoptosis repressor protein apoptosis repressor with caspase recruitment domain to lessen the extent of apoptosis. Hearts from adult male Sprague-Dawley rats were subjected to regional ischemia followed by reperfusion ex vivo, with mineralocorticoid receptor antagonists added to perfusates before ischemia. Low-dose spironolactone (10 nmol/L) or eplerenone (100 nmol/L) significantly reduced infarct size. Spironolactone also prevented cleavage of the apoptotic chromatin condensation inducer in the nucleus and of the inhibitor of caspase-activated DNAse induced by ischemia-reperfusion, thereby abolishing chromatin condensation and internucleosomal cleavage. Ischemia-reperfusion-induced activation of caspases 2, 3, and 9, but not caspase 8, was prevented by spironolactone, suggesting targeted regulation of the intrinsic pathway. Low-dose spironolactone and eplerenone prevented loss of the apoptosis repressor with the caspase recruitment domain and reduced myocyte death. In H9c2 cells, mineralocorticoid receptor activation by aldosterone resulted in apoptosis repressor with caspase recruitment domain degradation and enhanced apoptosis; these actions were prevented by coadministration of spironolactone. Using a triple lysine mutant we identified that aldosterone enhances posttranscriptional degradation of the apoptosis repressor with a caspase recruitment domain via the ubiquitin-proteasomal pathway. Our data demonstrate that low-dose mineralocorticoid receptor antagonists reduce infarct size and apoptosis in the reperfused myocardium by preventing the apoptosis repressor with caspase recruitment domain degradation. Key Words: myocardial infarction Ⅲ apoptosis Ⅲ ischemia Ⅲ reperfusion injury Ⅲ heart failure Ⅲ cardiovascular disease M ortality and morbidity after acute myocardial infarction remain high, despite rapid reperfusion by percutaneous coronary intervention, and additional therapeutic strategies that reduce infarct size are needed.1 Ischemia alters redox state triggering apoptosis and progressive loss of cardiomyocytes during and after myocardial infarction, which, in turn, contributes to developing congestive cardiac failure.2 Lowdose mineralocorticoid receptor (MR) antagonists have been shown clinically to reduce blood pressure, 3,4 particularly in resistant hypertension, and to substantially increase survival in heart failure, 5 heart failure after myocardial infarction, 6 and chronic systolic heart failure with mild symptoms. 7Significant benefits follow when eplerenone is administered early (Ͻ7 days) after myocardial infarction 8 and experimentally at reperfusion. 9,10 Interestingly, MR antagonists add...

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Low-Dose Spironolactone Prevents Apoptosis Repressor With Caspase Recruitment Domain Degradation During Myocardial Infarction

Mardini

Howell

et al. 2012

Hypertension

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“…One possibility is that caspase 2 is dispensable for nicotine-plus-HFD-induced CM apoptosis. A growing body of evidence indicates that an apoptosis repressor with caspase recruitment domain (ARC) is an endogenous apoptosis repressor protein that is highly expressed in cardiac tissue and that has the ability to inhibit ischemia-reperfusion (I-R)-induced CM apoptosis by targeting the activation of the intrinsic pathway at multiple points (Zhang and Herman 2006; Ludwig-Galezowski et al 2011; Le et al 2012). Conversely, the preservation of ARC levels is sufficient for CM viability after oxidative stress (Nam et al 2007) or infarction (Foo et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

et al. 2016

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Cigarette smoking is an important risk factor for diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The health risk associated with smoking can be aggravated by obesity. Smoking might also trigger cardiomyocyte (CM) apoptosis. Given that CM apoptosis has been implicated as a potential mechanism in the development of cardiomyopathy and heart failure, we characterize the key signaling pathways in nicotine plus high-fat diet (HFD)-induced CM apoptosis. Adult C57BL6 male mice were fed a normal diet (ND) or HFD and received twice-daily intraperitoneal (IP) injections of nicotine (0.75 mg/kg body weight [BW]) or saline for 16 weeks. An additional group of nicotine-treated mice on HFD received twice-daily IP injections of mecamylamine (1 mg/kg BW), a non-selective nicotinic acetylcholine receptor antagonist, for 16 weeks. Nicotine when combined with HFD led to a massive increase in CM apoptosis that was fully prevented by mecamylamine treatment. Induction of CM apoptosis was associated with increased oxidative stress and activation of caspase-2-mediated intrinsic pathway signaling coupled with inactivation of AMP-activated protein kinase (AMPK). Furthermore, nicotine treatment significantly (P < 0.05) attenuated the HFD-induced decrease in fibroblast growth factor 21 (FGF21) and silent information regulator 1 (SIRT1). We conclude that nicotine, when combined with HFD, triggers CM apoptosis through the generation of oxidative stress and inactivation of AMPK together with the activation of caspase-2-mediated intrinsic apoptotic signaling independently of FGF21 and SIRT1.

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“…In contrast, apoptosis repressor with caspase recruitment domain (ARC) specifically interferes with both the death receptor and the mitochondrial death pathways. ARC is a highly potent and multifunctional inhibitor of apoptosis that is physiologically expressed predominantly in postmitotic cells such as cardiac myocytes, skeletal muscle cells and neurons [94]. High cardiac expression makes ARC a unique and central cardiac death repressor [95].…”

Section: Endogenous Inhibitorsmentioning

confidence: 99%

Mechanisms and Inhibitors of Apoptosis in Cardiovascular Diseases

Singh¹,

Kang

2011

CPD

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Apoptosis or progress of programmed cell death is a tightly regulated process which plays an important role in various cardiovascular diseases particularly in myocardial infarction, reperfusion injury, and heart failure. Over the past two decades, investigations of several pathways have broadened our understanding of programmed cell death. Many anti-apoptotic interventions have targeted ischemia-reperfusion, however only a limited number have been considered at the chronic stage of heart failure. Endogenous inhibitors, caspase inhibitors, PARP-1 inhibitors, as well as various other agents have been implicated as anti-apoptotic interventions. This review summarizes the apoptotic pathways associated with heart failure, discusses the current anti-apoptotic interventions available and reviews the clinical implications.

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Apoptosis repressor with caspase recruitment domain, a multifunctional modulator of cell death

Cited by 43 publications

References 60 publications

Low-Dose Spironolactone Prevents Apoptosis Repressor With Caspase Recruitment Domain Degradation During Myocardial Infarction

Low-Dose Spironolactone Prevents Apoptosis Repressor With Caspase Recruitment Domain Degradation During Myocardial Infarction

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

Mechanisms and Inhibitors of Apoptosis in Cardiovascular Diseases

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