Inhibition of Copper-Zinc Superoxide Dismutase Induces Cell Growth, Hypertrophic Phenotype, and Apoptosis in Neonatal Rat Cardiac Myocytes In Vitro

Siwik, Deborah A.; Tzortzis, John D.; Pimental, David R.; Chang, Donny L.F.; Pagano, Patrick J.; Singh, Krishna; Sawyer, Douglas B.; Colucci, Wilson S.

doi:10.1161/01.res.85.2.147

Cited by 252 publications

(155 citation statements)

References 26 publications

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“…8). DDC inhibition of superoxide dismutase has been shown to increase superoxide generation in neonatal rat cardiac myocytes (24), and we demonstrated that the caspase-3-like activity of both oleate-and palmitate-incubated cells increased in the presence of increasing concentrations of DDC (Table 2). However, the caspase-3-like activity of oleate-treated cells in the presence of DDC, even at a concentration (100 M) previously shown to induce apoptosis (24), never attained the levels achieved by palmitate incubation alone (without DDC).…”

Section: Nf-b Binding Activity and Effect Of Superoxide Dismutase Inhmentioning

confidence: 53%

Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Hickson-Bick¹,

Sparagna²,

Buja³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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The saturated fatty acid palmitate induces apoptosis in neonatal rat cardiomyocytes. This apoptosis is associated with early mitochondrial release of cytochrome c and a subsequent loss of mitochondrial membrane potential. Recent reports implicate a role for reactive oxygen species (ROS) in palmitate-induced apoptosis. We studied the role of ROS in palmitate-induced apoptosis in the neonatal rat cardiomyocyte and report no evidence of ROS involvement. ROS production, nitric oxide production, and nuclear factor-B activation were not increased above those observed using the nonapoptotic fatty acid oleate. Indeed, the production of ROS was significantly higher in cells treated with oleate. Furthermore, the presence of antioxidants and ROS scavengers did not attenuate the induction of apoptosis by palmitate. Variations in the fatty acid-to-albumin ratio from 2:1 to 7:1 had no effect on the absence of ROS production or on the extent of apoptosis. No evidence was found for an increase in oxidative protein modification in palmitate-treated cells. Our results lead us to conclude that oxidative stress does not play a role in palmitate-induced apoptosis.antioxidants; nitric oxide; mitochondria; nuclear factor-B

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Section: Nf-b Binding Activity and Effect Of Superoxide Dismutase Inhmentioning

confidence: 53%

Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Hickson-Bick¹,

Sparagna²,

Buja³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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show abstract

“…[2][3][4][5][6][7][8][9] Experimental studies have shown the beneficial effects of antioxidants for prevention of heart failure. 5,14,32 However, the effectiveness of antioxidants for human patients with heart failure has not been clarified.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Furthermore, we and other investigators have reported that ROS have important functions in apoptosis and cytokine-stimulated hypertrophy of cardiac myocytes. 4,5 Clinical studies have also revealed that lipid peroxides and 8-iso-prostaglandin F2␣, which are the major biochemical products of ROS generation, are elevated in plasma and pericardial fluid of patients with heart failure. 6 -9 However, direct evidence of oxidative stress elevation in the human myocardium has not been obtained.…”

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confidence: 99%

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

et al. 2002

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Background-Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating ␤-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results-Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (PϽ0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9Ϯ4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22Ϯ8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (PϽ0.005) along with amelioration of heart failure. Conclusions-Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

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“…12,17 Furthermore, other reports have shown that loss of SOD can initiate apoptosis in some cell types, 29 therefore we hypothesized that diminished SOD in airway epithelial cells might be a central event mediating airway epithelial cell apoptosis. To address whether inactivation of SOD and/or increasing reactive oxygen species play a role in airway apoptosis, we treated BET1A cells with pyrogallol, a superoxide-producing agent, 2-ME, a SOD activity inhibitor or hydrogen peroxide, in a dose-and time-dependent manner.…”

Section: Effects Of Oxidative Stress On Airway Epithelial Cellsmentioning

confidence: 96%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

171

148

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Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

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Inhibition of Copper-Zinc Superoxide Dismutase Induces Cell Growth, Hypertrophic Phenotype, and Apoptosis in Neonatal Rat Cardiac Myocytes In Vitro

Cited by 252 publications

References 26 publications

Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

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