Myocardial oxidative stress contributes to transgenic β<sub>2</sub>‐adrenoceptor activation‐induced cardiomyopathy and heart failure

Xu, Qi; Dalic, Andrea; Lü, Fang; Kiriazis, Helen; Ritchie, Rebecca H; Sim, Kenneth; Gao, Xiao‐Ming; Drummond, Grant Raymond; Sarwar, Muhammad Usman; Zhang, Youyi; Dart, Anthony M.; Du, Xiao‐Jun

doi:10.1111/j.1476-5381.2010.01043.x

Cited by 108 publications

(124 citation statements)

References 52 publications

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“…Hearts were fixed in 10% formalin in phosphate-buffered saline, paraffin-embedded, serially sectioned (5 mM) and stained with Picrosirius red or Masson's trichrome. 58 Echocardiography. Animals were anesthetized by isoflurane.…”

Section: Methodsmentioning

confidence: 99%

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CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

et al. 2013

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Catecholamines regulate the b-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the b-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. Cell Death and Differentiation (2013) 20, 941-952; doi:10.1038/cdd.2013 published online 12 April 2013 Cyclic adenosine monophosphate (cAMP) is a second messenger that is highly conserved throughout evolution. In metazoans, its primary role is to act as an intracellular carrier of metabolic information, regulating hormonal responses, 1 in triggering apoptotic cell death and in regulating ontogeny.2,3

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Section: Methodsmentioning

confidence: 99%

“…LV fractional shortening was calculated from LV diameters at the diastole and systole from the M-mode traces derived from 2D image, as described before. 58 Promoter methylation analysis. Promoter methylation was analysed by bisulphite sequencing of the BIM promoter using MethylDetector kit (Active Motif, Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

et al. 2013

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“…22,23,[27][28][29] LV function and dimensions were assessed via 2-dimensional M-mode and Doppler echocardiography (using 15-MHz linear array and 12-MHz sector transducers, respectively). Doppler transmitral echocardiography allowed assessment of LV diastolic filling (LV E:A, the ratio of peak early, E, and late atrial, and A, transmitral blood flow velocities), deceleration time of early (E) velocity and isovolumic relaxation times.…”

Section: Echocardiography For Analysis Of LV Function In Mice In Vivomentioning

confidence: 99%

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Cao

Wong

Rosli

et al. 2015

Circ: Heart Failure

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Background-Nitroxyl (HNO), a redox congener of nitric oxide (NO•), is a novel regulator of cardiovascular function, combining concomitant positive inotropic, lusitropic, and vasodilator properties. Moreover, HNO exhibits myocardial antihypertrophic and superoxide-suppressing actions. Despite these favorable actions, the impact of chronic HNO administration has yet to be reported in the context of cardiomyopathy. Diabetic cardiomyopathy is characterized by early diastolic dysfunction and adverse left ventricular (LV) structural remodeling, with LV superoxide generation playing a major causal role. We tested the hypothesis that the HNO donor 1-nitrosocyclohexylacetate (1-NCA) limits cardiomyocyte hypertrophy and LV diastolic dysfunction in a mouse model of diabetes mellitus in vivo. Methods and Results-Diabetes mellitus was induced in male FVB/N mice using streptozotocin. After 4 weeks, diabetic and nondiabetic mice were allocated to 1-NCA therapy (83 mg/kg per day IP) or vehicle and followed up for a further 4 weeks. Diabetes mellitus-induced LV diastolic dysfunction was evident on echocardiography-derived E and A wave velocities, E:A ratio, deceleration, and isovolumic relaxation times; LV systolic function was preserved. Increased LV cardiomyocyte size, hypertrophic and profibrotic gene expression, and upregulation of LV superoxide were also evident. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as an HNO donor was demonstrated by sensitivity of acute 1-NCA to L-cysteine but not to hydroxocobalamin in the normal rat heart ex vivo. Conclusions-Our studies provide the first evidence that HNO donors may represent a promising strategy for treatment of diabetic cardiomyopathy and implies therapeutic efficacy in settings of chronic heart failure. (Circ Heart Fail. 2015;8:572-581.

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“…Apoptosis was determined by counting over 1000 cardiomyocyte nuclei per LV, as described previously. 24,25 Additionally, the effects of MI and RLX on angiogenesis were evaluated by counting the a-SMA-and Glut-1 (in structures that histologically resembled capillaries)-stained blood vessels in the NIR and BR of the various groups studied, and were expressed as the number of blood vessels per field. All analyses were independently performed by two investigators, in a blinded manner (and the data averaged in each case).…”

Section: Histology and Morphometric Analysismentioning

confidence: 99%

Relaxin remodels fibrotic healing following myocardial infarction

Samuel

Cendrawan

Gao

et al. 2011

Laboratory Investigation

101

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In the setting of myocardial infarction (MI), implanted stem cell viability is low and scar formation limits stem cell homing, viability, and integration. Thus, interventions that favorably remodel fibrotic healing may benefit stem cell therapies. However, it remains unclear whether it is feasible and safe to remodel fibrotic healing post-MI without compromising ventricular remodeling and dysfunction. This study, therefore, determined the anti-fibrotic and other effects of the hormone, relaxin in a mouse model of MI. Adult male mice underwent left coronary artery ligation-induced MI and were immediately treated with recombinant human relaxin (MI þ RLX) or vehicle (MI þ VEH) over 7 or 30 days, representing time points of early and mature fibrotic healing. Cardiac function was assessed by echocardiography and catheterization, while comprehensive immunohistochemistry, morphometry, and western blotting were performed to explore the relaxin-induced mechanisms of action post-MI. RLX significantly inhibited the MI-induced progression of cardiac fibrosis over 7 and 30 days, which was associated with a reduction in TGF-b1 expression, myofibroblast differentiation, and cardiomyocyte apoptosis in addition to a promotion of matrix metalloproteinase-13 levels and de novo blood vessel growth (all Po0.05 vs respective measurements from MI þ VEH mice). Despite the evident fibrotic healing post-MI, relaxin did not adversely affect the incidence of ventricular free-wall rupture or the extent of LV remodeling and dysfunction. These combined findings demonstrate that RLX favorably remodels the process of fibrotic healing post-infarction by lowering the density of mature scar tissue in the infarcted myocardium, border zone, and non-infarcted myocardium, and may, therefore, facilitate cell-based therapies in the setting of ischemic heart disease.

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Myocardial oxidative stress contributes to transgenic β₂‐adrenoceptor activation‐induced cardiomyopathy and heart failure

Cited by 108 publications

References 52 publications

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Relaxin remodels fibrotic healing following myocardial infarction

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Myocardial oxidative stress contributes to transgenic β2‐adrenoceptor activation‐induced cardiomyopathy and heart failure

Cited by 108 publications

References 52 publications

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Relaxin remodels fibrotic healing following myocardial infarction

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Myocardial oxidative stress contributes to transgenic β₂‐adrenoceptor activation‐induced cardiomyopathy and heart failure