Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression

Bouma, Wobbe; Noma, Mio; Kanemoto, Shinya; Matsubara, Muneaki; Leshnower, Bradley G.; Hinmon, Robin; Gorman, rd Joseph H.; Gorman, Robert C.

doi:10.1152/ajpheart.01021.2009

Cited by 27 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Further, in Tg(cmlc2:nucDsRed) zebrafish we found evidence of myocardial cell apoptosis and necrosis; at the 18 h time point, ∼10% of cardiomyocytes were TUNEL + and ∼15% of cardiomyocytes were necrotic as evidenced by AO staining. Both the time course and the magnitude of cell death observed in zebrafish are comparable to what has been shown to occur in the mammalian heart [29].…”

Section: Discussionsupporting

confidence: 70%

Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart

et al. 2013

View full text Add to dashboard Cite

Aimsthe adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it.Methods and Resultsadult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2–6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL+ and 15.0±2.5% were AO+. At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18–24 h after H/R, it achieved its peak 3–7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3+ and 7.4±0.6% were PCNA+ (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point).Conclusionszebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models.

show abstract

Section: Discussionsupporting

confidence: 70%

Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In a mouse model of acute MI, males have delayed myocardial healing, higher infarct re-expansion, and an increased risk of cardiac rupture [23]. In females, endogenous estrogens (biologically active 17-β-estradiol) have been demonstrated to aid in limiting cardiac apoptosis, thereby resulting in reduced infarct size in response to ischemia/ reperfusion injury [24,25]. While this is an area of intense ongoing investigation, estrogens may mediate a large portion of the observed sex differences in response to acute coronary ischemia and reperfusion.…”

Section: Burden Of Ischemic Heart Disease In Men and Women Prevalencementioning

confidence: 99%

Gender Differences in the Pathophysiology, Clinical Presentation, and Outcomes of Ischemic Heart Failure

Dunlay

Roger

2012

Curr Heart Fail Rep

View full text Add to dashboard Cite

Despite advances in the treatment of acute myocardial infarction (MI), heart failure (HF) remains a frequent acute and long-term outcome of ischemic heart disease (IHD). In response to acute coronary ischemia, women are relatively protected from apoptosis, and experience less adverse cardiac remodeling than men, frequently resulting in preservation of left ventricular size and ejection fraction. Despite these advantages, women are at increased risk for HF-complicating acute MI when compared with men. However, women with HF retain a survival advantage over men with HF, including a decreased risk of sudden death. Sex-specific treatment of HF has been hindered by historical under-representation of women in clinical trials, though recent work has suggested that women may have a differential response to some therapies such as cardiac resynchronization. This review highlights the sex differences in the pathophysiology, clinical presentation and outcomes of ischemic heart failure and discusses key areas worthy of further investigation.

show abstract

“…ARC levels were also shown to drop following hypoxia/reoxygenation in cultured rat cardiomyocytes, a loss which can, however, be counteracted by repeated short post-conditioning cycles of hypoxia/reoxygenation [28]. Interestingly, a recent study conducted in rabbits suggested that endogenous levels of oestrogen mediate a constitutively higher ARC expression in the heart tissue of female individuals, which confers elevated apoptosis resistance in response to ischaemia/reperfusion and might explain the enhanced myocardial recovery of female individuals [29]. …”

Section: (Patho)physiology and Arc Expressionmentioning

confidence: 99%

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

Ludwig-Gałęzowska

Flanagan

Rehm

2011

Journal of Cellular and Molecular Medicine

View full text Add to dashboard Cite

Apoptosis repressor with caspase recruitment domain (ARC) is a highly potent and multifunctional inhibitor of apoptosis that is physiologically expressed predominantly in post-mitotic cells such as cardiomyocytes, skeletal muscle cells and neurons. ARC was also found to be up-regulated in many forms of malignant tumours. ARC impairs the cellular apoptotic responsiveness to a wide range of stresses and insults, including extrinsic apoptosis initiation via death receptor ligands, dysregulation of cellular Ca2+ homeostasis and endoplasmatic reticulum (ER) stress, genotoxic drugs, ionizing radiation, oxidative stress and hypoxia. ARC is subject to both transcriptional and post-translational regulation and exhibits its function through a multitude of molecular interactions with upstream transducers of apoptosis signals. This review summarizes, structures and comments on the published knowledge regarding ARC and its roles in modulating apoptotic cell death responsiveness in physiological and pathophysiological contexts.

show abstract

Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression

Cited by 27 publications

References 44 publications

Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart

Hypoxia/Reoxygenation Cardiac Injury and Regeneration in Zebrafish Adult Heart

Gender Differences in the Pathophysiology, Clinical Presentation, and Outcomes of Ischemic Heart Failure

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

Contact Info

Product

Resources

About