p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes.

Long, Xilin; Boluyt, Marvin O.; Hipolito, Maria De Lourdes; Lundberg, Martha S.; Zheng, Jun; O’Neill, Lydia; Cirielli, Corrado; Lakatta, Edward G.; Crow, Michael T.

doi:10.1172/jci119452

Cited by 285 publications

(221 citation statements)

References 36 publications

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“…This suggests that mitochondria control the progression of death receptor-dependent PCD in fibroblasts and, by blocking this death pathway, cardiac fibroblasts are protected against a wide range of death stimuli. Furthermore, our data (showing resistance of cardiac fibroblasts up to 3 days from glucose and serum deprivation plus hypoxia) go beyond a previous report describing the lack of DNA degradation after 48 h of hypoxia alone (24). These findings are of pathophysiological relevance because cardiac fibroblasts play an important role in the healing of the ischemic lesion, where the drop in local oxygen tension is accompanied by a restriction in serum and glucose availability.…”

Section: Discussionsupporting

confidence: 69%

“…This observation implies that cardiac fibroblasts are able to endure and secrete the ECM that constitutes the fibrotic scar under situations that threaten survival of other cell types. Consistent with the enhanced survival potential of cardiac fibroblasts, it has been reported that these cells have reduced apoptosis and sustained proliferation during hypoxia (24), alcohol exposure (25), and oxidative stress (26,27). However, the molecular mechanisms underlying the resistance of cardiac fibroblasts to stimuli inducing cell death are presently unknown.…”

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confidence: 88%

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Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Mayorga

Bahí

Ballester

et al. 2004

Journal of Biological Chemistry

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Cardiac fibroblasts play an essential role in the physiology of the heart. These produce extracellular matrix proteins and synthesize angiogenic and cardioprotective factors. Although fibroblasts of cardiac origin are known to be resistant to apoptosis and to remain metabolically active in situations compromising cell survival, the underlying mechanisms are unknown. Here, we report that cardiac fibroblasts were more resistant than dermal or pulmonary fibroblasts to mitochondriadependent cell death. Cytochrome c release was blocked in cardiac fibroblasts but not in dermal fibroblasts treated with staurosporine, etoposide, serum deprivation, or simulated ischemia, precluding caspase-3 activation and DNA fragmentation. Resistance to apoptosis of cardiac fibroblasts correlated with the expression of the anti-apoptotic protein Bcl-2, whereas skin and lung fibroblasts did not express detectable levels of this protein. Bcl-x L, Bax, and Bak were expressed at similar levels in cardiac, dermal, and lung fibroblasts. In addition, the death of cardiac fibroblasts during hypoxia was not associated with the cleavage of Bid but rather with Bcl-2 disappearance, suggesting the requirement of the mitochondrial apoptotic machinery to execute death receptor-induced programmed cell death. Knockdown of bcl-2 expression by siRNA in cardiac fibroblasts increased their apoptotic response to staurosporine, serum, and glucose deprivation and to simulated ischemia. Moreover, dermal fibroblasts overexpressing Bcl-2 achieved a similar level of resistance to these stimuli as cardiac fibroblasts. Thus, our data demonstrate that Bcl-2 is an important effector of heart fibroblast resistance to apoptosis and highlight a probable mechanism for promoting survival advantage in fibroblasts of cardiac origin.

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Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 88%

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Mayorga

Bahí

Ballester

et al. 2004

Journal of Biological Chemistry

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“…44,45 However, the molecular mechanism through which hypoxia induces apoptosis is far from clear. Through microarray analysis of a neonatal rat cardiomyocyte subtracted cDNA library, we demonstrated that expression of the pro-apoptotic gene BNIP3 is dramatically upregulated during hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces the expression of the pro-apoptotic gene BNIP3

Guo¹,

Searfoss²,

Krolikowski³

et al. 2001

Cell Death Differ

298

222

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It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene BNIP3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1a, but not p53, induces the expression of BNIP3. Overexpression of BNIP3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of BNIP3 may play a significant role during hypoxiainduced cell death. Cell Death and Differentiation (2001) 8, 367 ± 376.

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“…45 Other reports observed neonatal myocyte cell loss after 24-72 h of hypoxia. 46 In contrast, one study found that rapidly contracting neonatal cardiac myocytes have very minimal cell death for up to 5 days under hypoxic conditions. 47 Nevertheless, neonatal cardiac myocytes have been identified to be more resistant to hypoxia than adult cardiac myocytes, demonstrated by the significant myocardial apoptosis in adult mice subjected to hypoxia.…”

Section: Bnip3mentioning

confidence: 95%

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

2009

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Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Bcl-2 nineteen-kilodalton interacting protein (BNIP3) belongs to the Bcl-2 homology domain (BH3)-only Bcl-2 family members because it only contains a putative BH3 domain. 1 The other major domains found in BNIP3 are the PEST domain that targets BNIP3 for degradation, a conserved domain that is conserved from Caenorhabditis elegans to humans and a transmembrane (TM) domain, which targets BNIP3 to the mitochondria (Figure 1). 2 BH3-only containing proteins act as rheostats regulating apoptosis through their BH3 domain by binding to antiapoptotic Bcl-2 family members. However, BNIP3 differs from these members, as its BH3 domain fails to interact with antiapoptotic Bcl-2 family members. 3 Furthermore, deletions of the BH3 domain fail to affect the ability of BNIP3 to induce cell death. 4 Unlike other BH3-only family members, BNIP3 interacts with Bcl-2 and Bcl-X L through its TM domain and N terminus (amino acids 1-49). 3 Deletion of the TM domain blocks the ability of BNIP3 to induce cell death. 4 BNIP3 migrates at 30 and 60 kDa, indicating that BNIP3 is a protein that forms homodimers. This homodimerization is primarily through the TM domain of BNIP3. The unique structure of the TM domain suggests that BNIP3 dimers could act as proton channels in the outer mitochondrial membrane increasing ion conductance. 5 Serine 172 and histidine (His) 173 are residues that are present in the dimerization interface of BNIP3. These residues interact by hydrogen bonds and are essential for dimer formation. 6 Furthermore, mutation of the His 173 to alanine completely abrogated the ability of BNIP3 to induce cell death. 7 Bcl-2 and Bcl-X L can compete for binding to the TM domain, which blocks BNIP3 homodimerization and abrogates the ability of BNIP3 to induce cell death (Fi...

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p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes.

Cited by 285 publications

References 36 publications

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Bcl-2 Is a Key Factor for Cardiac Fibroblast Resistance to Programmed Cell Death

Hypoxia induces the expression of the pro-apoptotic gene BNIP3

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

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