p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on <scp>NOS</scp>3 promoter through regulation of p53‐<scp>L</scp>ys<sup>118</sup> acetylation

Gogna, Rajan; Madan, Esha; Khan, Mahmood; Pati, Uttam; Kuppusamy, Periannan

doi:10.1002/emmm.201202055

Cited by 31 publications

(17 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, because Brn-3a can also block p53-mediated apoptosis, it may enhance other p53 target genes, such as NOS3, which is associated with survival in oxygenated myocardium outside the infarct zone. 60 In this regard, although Brn-3a inhibits p53-mediated apoptic genes, it may cooperate with p53 to regulate distinct target genes that promote survival of specific cell populations that might affect long-term outcome in the injured heart.…”

Section: Discussionmentioning

confidence: 99%

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Budhram-Mahadeo¹,

Fujita²,

Bitsi³

et al. 2014

Cell Death Dis

View full text Add to dashboard Cite

Cardiomyocyte death following ischaemic/hypoxic injury causes irreversible damage to cardiac function and contributes to chronic diseases such as heart failure. Understanding the mechanisms associated with myocyte loss under these conditions can help to identify strategies to minimise/abrogate such detrimental effects. The p53 protein can induce apoptosis or cell cycle arrest, but effects on cell fate depend on interactions with other regulators such as POU4F2/Brn-3b (Brn-3b), which co-operates with p53 to increase the expression of pro-apoptotic genes. In contrast, the related POU4F1/Brn-3a (Brn-3a) blocks p53-mediated apoptosis but co-operates with p53 to enhance cell cycle arrest. In this study, we showed that permanent coronary artery ligation in mouse hearts, which induced apoptotic markers, activated caspase-3 and -8 and necroptosis markers; RIP-1 and -3 also increased Brn-3b and Brn-3a expression. However, Brn-3a was only detected in uninjured myocardium but not at the site of injury, whereas Brn-3b showed generalised increase, including within the infarct zone. Conversely, p53 was detected in the infarct zone and in some cells adjacent to the site of injury but not in uninjured myocardium. Co-localisation studies showed Brn-3a co-expression with p53 in cardiomyocytes adjacent to the infarct zone, whereas Brn-3b was co-localised with p53 in the infarct zone only. Increased Brn-3b and p53 correlated with elevated expression of pro-apoptotic target genes, Bax, Noxa and PUMA, whereas cleaved caspase-3 confirmed the presence of apoptotic cells within this region of the injured heart. Similarly, simulated ischaemia/reoxygenation (sI/R) injury in neonatal rat ventricular cardiomyocytes (NRVM) and heart derived H9c2 myoblasts increased Brn-3b, p53 as well as apoptotic genes, and this was associated with enhanced apoptosis. Furthermore, targeted reduction of Brn-3b using shRNA caused reduction in pro-apoptotic Bax and Noxa proteins, even though p53 expression remained intact, suggesting that Brn-3b is important for controlling the fate of the myocardium in the injured heart.

show abstract

Section: Discussionmentioning

confidence: 99%

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Budhram-Mahadeo¹,

Fujita²,

Bitsi³

et al. 2014

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…The stabilized DNA-binding domain (residues 94-312) of the p53 mutant Y220C (T-p53C-Y220C) and T-p53C cysteine mutants (C124S/C277S, C124S/C182S, and C182S/C277S) were expressed and purified as described (60).…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

Madan

Parker

Bauer

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…We addressed this by testing whether, in DCM, the oxygenation response to stress is appropriate, and whether resting cardiac function and high-energy phosphate metabolism are improved with inhaled supplemental oxygen (increasing myocardial oxygenation as has been validated in animal models). 12 If this were the case, then mechanisms to improve oxygen delivery and use would be important targets for therapeutic intervention in treating patients with chronic heart failure because of DCM. To do so, we exploited hemoglobin’s differences in magnetic susceptibility in its diamagnetic oxygenated and paramagnetic deoxygenated state (oxygenation-sensitive cardiovascular magnetic resonance [CMR] imaging).…”

mentioning

confidence: 99%

No Evidence of Myocardial Oxygen Deprivation in Nonischemic Heart Failure

Dass

Holloway

Cochlin

et al. 2015

Circ: Heart Failure

View full text Add to dashboard Cite

Background—Whether the myocardium in nonischemic heart failure experiences oxygen limitation remains a long-standing controversy. We addressed this question in patients with dilated cardiomyopathy (DCM) using a dual approach. First, we tested the changes in myocardial oxygenation between rest and stress states, using oxygenation-sensitive cardiovascular magnetic resonance. Second, we sought to assess the functional consequences of oxygen limitation at rest by measuring myocardial energetics before and after short-term oxygen supplementation.Methods and Results—Twenty-six subjects (14 DCM and 12 normal) underwent cardiac magnetic resonance imaging at 3 Tesla to assess cardiac volumes, function, oxygenation, and first-pass perfusion (0.03 mmol/kg Gd-DTPA bolus) at stress and rest (4–6 minutes IV adenosine, 140 μg/kg per minute). Signal intensity change (SIΔ) and myocardial perfusion reserve index (MPRI) were measured from oxygenation and perfusion images, respectively. Furthermore, the effect of oxygen supplementation on resting myocardial energy metabolism was tested using 31P MR spectroscopy, measuring PCr/ATP ratios in both groups at baseline and after 4 hours of oxygen via facemask in the DCM group. During stress, there were equivalent rises in rate pressure product in both groups (DCM, 76±15% and normal, 79±9%; P=0.84). MPRI was significantly reduced in DCM (1.51±0.11 versus normal 1.86±0.10; P=0.03). However, there was no difference in oxygenation between groups: SIΔ in DCM 17±3% versus normal 20±2% (P=0.38). Furthermore, at a left ventricular segmental level, there was no correlation between oxygenation-sensitive SIΔ and MPRI (R=0.06; P=0.43). Resting PCr/ATP was reduced in DCM (1.66±0.07 versus normal 2.12±0.06; P=0.002). With oxygen supplementation, there was no change in PCr/ATP (1.61±0.08; P=0.58; Δ=0.04±0.05). There was also no effect of oxygen on systolic function (ejection fraction pre oxygen, 34±1%; post oxygen, 36±2%; P=0.46; Δ 2±1%).Conclusions—Our results demonstrate dissociation between microvascular dysfunction and oxygenation in DCM, suggesting that the impairment of perfusion is not sufficient to cause deoxygenation during stress. Cardiac energetics are unaffected by oxygen supplementation, indicating the absence of relevant myocardial hypoxia at rest. Our study suggests that novel treatments for nonischemic heart failure should focus on efforts to directly target cardiomyocyte function and metabolism rather than oxygen delivery and microvascular function.

show abstract

p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53‐Lys¹¹⁸ acetylation

Cited by 31 publications

References 75 publications

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

No Evidence of Myocardial Oxygen Deprivation in Nonischemic Heart Failure

Contact Info

Product

Resources

About

p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53‐Lys118 acetylation

Cited by 31 publications

References 75 publications

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

No Evidence of Myocardial Oxygen Deprivation in Nonischemic Heart Failure

Contact Info

Product

Resources

About

p53's choice of myocardial death or survival: Oxygen protects infarct myocardium by recruiting p53 on NOS3 promoter through regulation of p53‐Lys¹¹⁸ acetylation