Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy

Shaw, James; Kirshenbaum, Lorrie A.

doi:10.4161/auto.5901

Cited by 33 publications

(22 citation statements)

References 75 publications

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“…In particular, this finding argues that the cardiac phenotype is not merely a secondary consequence of chronic volume overload and hyperviscosity. Morever, we observed the loss of mitochondria in Phd-deficient and pVHL-deficient hearts, as well as increased transcription of Bnip3, which has been implicated in mitochondrial autophagy (14,46,48,55). These data are consistent with Phd loss causing cardiomyopathy because of a cardiomyocyte-specific role for Phd in the control of mitochondrial autophagy.…”

Section: Discussionsupporting

confidence: 76%

A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo

Minamishima

Moslehi

Padera

et al. 2009

Molecular and Cellular Biology

145

132

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Hypoxia-inducible factor (HIF), consisting of a labile ␣ subunit and a stable ␤ subunit, is a master regulator of hypoxia-responsive mRNAs. HIF␣ undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase. Phd3 is induced by HIF and, based on findings from in vitro studies, may participate in a HIF-regulatory feedback loop. Here, we report that Phd3 loss exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and produces a closer phenocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone. Importantly, the degree to which Phd3 can compensate for Phd2 loss and the degree to which the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive genes and in different tissues. These findings highlight that the responses of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific prolyl hydroxylase inhibitors as therapeutic agents.Many human diseases, including anemia, myocardial infarction, and stroke, are closely linked to tissue hypoxia. The transcriptional response to hypoxia in metazoans is mediated primarily by the heterodimeric transcriptional factor hypoxiainducible factor (HIF), which consists of an ␣ subunit (HIF␣) and a ␤ subunit (HIF␤, also called the aryl hydrocarbon receptor nuclear translocator) (21). Under hypoxic conditions, HIF␣ accumulates, dimerizes with HIF␤, translocates to the nucleus, and transcriptionally activates genes containing hypoxia response elements. Many of these genes regulate processes, such as erythropoiesis, angiogenesis, and energy metabolism, that affect oxygen delivery or oxygen consumption and thereby affect survival in a low-oxygen environment (47).There are three HIF␣ family members in humans, called HIF1␣, HIF2␣, and HIF3␣. Both HIF1␣ (the canonical HIF␣ family member) and HIF2␣ contain two transactivation domains, the N-terminal transactivation domain (NTAD) and the C-terminal transactivation domain (CTAD), and can activate transcription when bound to DNA. Whether HIF3␣ activates transcription is less certain. Multiple HIF3␣ splice variants have been identified, at least some of which are dominantinterfering with respect to HIF␣ activity (31, 32).The mechanism that couples the accumulation of HIF␣ to oxygen availability has recently come into view. When oxygen is plentiful, HIF␣ becomes hydroxylated at one (or both) of two conserved prolyl residues (21). HIF␣ hydroxylated at one prolyl residue is recognized by a ubiquitin ligase complex that contains the von Hippel-Lindau tumor suppressor protein (pVHL), polyubiquitinated, and degraded by the proteasome. Caenorhabditis elegans and Drosophila species contain a single prolyl hydroxylase, calle...

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Section: Discussionsupporting

confidence: 76%

A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo

Minamishima

Moslehi

Padera

et al. 2009

Molecular and Cellular Biology

145

132

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“…Previous work by our laboratory identified the inducible protein Bnip3 sufficient to provoke autophagy and cell death of ventricular myocytes during ischemic and hypoxic stress. 14,26 We attributed this to the loss of mitochondrial ΔΨ m and mPTP opening. The fact that Bnip3 gene and protein expression were increased by p53 is compelling and identifies Bnip3 as putative down-stream effector of p53.…”

Section: Discussionmentioning

confidence: 99%

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

et al. 2013

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Abstract-Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death.Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial ∆Ψ m . This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53-indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3 −/− mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.

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“…to heart failure is postulated to involve the continued loss of functional cardiac myocytes through pathways of cell death, including necrosis, apoptosis, and autophagy, 3,4 which results in replacement of myocytes by scar tissue or diffuse interstitial fibrosis. Early loss of cardiac myocytes is likely the combination of ischemia-induced necrosis, ischemia/reperfusion injury, and apoptosis.…”

mentioning

confidence: 99%

Multiple Facets of NF-κB in the Heart

Gordon

Shaw

Kirshenbaum

2011

Circulation Research

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496

309

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Abstract:The progression from cardiac injury to symptomatic heart failure has been intensely studied over the last decade, and is largely attributable to a loss of functional cardiac myocytes through necrosis, intrinsic and extrinsic apoptosis pathways and autophagy. Therefore, the molecular regulation of these cellular programs has been rigorously investigated in the hopes of identifying a potential cell target that could promote cell survival and/or inhibit cell death to avert, or at least prolong, the degeneration toward symptomatic heart failure. The nuclear factor (NF)-B super family of transcription factors has been implicated in the regulation of immune cell maturation, cell survival, and inflammation in many cell types, including cardiac myocytes. Recent studies have shown that NF-B is cardioprotective during acute hypoxia and reperfusion injury. However, prolonged activation of NF-B appears to be detrimental and promotes heart failure by eliciting signals that trigger chronic inflammation through enhanced elaboration of cytokines including tumor necrosis factor ␣, interleukin-1, and interleukin-6, leading to endoplasmic reticulum stress responses and cell death. The underlying mechanisms that account for the multifaceted and differential outcomes of NF-B on cardiac cell fate are presently unknown. Herein, we posit a novel paradigm in which the timing, duration of activation, and cellular context may explain mechanistically the differential outcomes of NF-B signaling in the heart that may be essential for future development of novel therapeutic interventions designed to target NF-B responses and heart failure following myocardial injury. (Circ Res. 2011;108:1122-1132.)

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Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy

Cited by 33 publications

References 75 publications

A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo

A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo

p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

Multiple Facets of NF-κB in the Heart

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