Effect of β-Blockers on Free Radical–Induced Cardiac Contractile Dysfunction

Flesch, Markus; Maack, Christoph; Cremers, Bodo; Bäumer, Anselm T.; Südkamp, Michael; Böhm, Michael

doi:10.1161/01.cir.100.4.346

Cited by 119 publications

(83 citation statements)

References 38 publications

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“…17 Carvedilol prevented hydroxyl radical-induced cardiac contractile dysfunction in human myocardial tissue, but metoprolol did not. 18 These results suggest the possible importance of the use of carvedilol. Third, a recent study has revealed that carvedilol inhibits ROS generation by leukocytes.…”

Section: Discussionmentioning

confidence: 92%

“…Carvedilol inhibits Fe 2ϩ -initiated lipid peroxidation and partially prevents hydroxyl radical-induced cardiac contractile dysfunction. 17,18 Carvedilol may reduce the oxidative stress level in the human failing myocardium via such various mechanisms. This study therefore was designed to determine whether carvedilol reduces the levels of HNE-modified protein in myocardia of patients with DCM.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

et al. 2002

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“…This observation is in close agreement with previous reports. [1][2][3]7,8,23 In rabbit myocardium, hydroxyl radical exposure leads to a degradation of TnT, associated with an increased calcium sensitivity of the myofilaments. However, inhibition of the calcium-dependent protease calpain I abolishes this TnT degradation and preserves calcium sensitivity, but it does not diminish acute diastolic dysfunction after hydroxyl radical exposure significantly.…”

Section: Discussionmentioning

confidence: 99%

“…Oxygen free radicals occurring during reperfusion after ischemia are thought to be involved in the development of "stunned myocardium" and in the development and progression of heart failure are associated with increased oxidative stress. [3][4][5][6] Free radical-induced myocardial dysfunction is characterized on different biological levels: oxygen free radical-exposed myocardial tissue and single cells show a severe diastolic dysfunction, 1,2 and contracting intact cardiac trabeculae from rabbit 7 and human 8 develop a rigor-like contracture marked by a severe and in part reversible increase in diastolic force and a loss of developed force. However, the mechanisms whereby oxidative stress acts remain speculative.…”

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confidence: 99%

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

Zeitz

Maass²,

Nguyen³

et al. 2002

Circulation Research

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Abstract-Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca 2ϩ levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (F dia ) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca 2ϩ (EC 50 : 3.27Ϯ0.24ϫ10Ϫ6 versus 2.69Ϯ0.15ϫ10 Ϫ6 mol/L; PϽ0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca 2ϩ sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540Ϯ93%) and pharmacologically blocked sarcoplasmic reticulum (539Ϯ77%), and was also similar in presence of the L-type Ca 2ϩ -channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca 2ϩ sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca 2ϩ influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.

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“…Apoptosis can be induced by DNA damage and p53 up-regulation [6] which is affected by oxidative stress. Oxidative stress due to reactive oxygen species (ROS) takes part in oxygen toxicity causing damage to cellular and subcellular organelles such as the cellular membrane [7,8] and mitochondria [9] or sarcoplasmic reticulum [10] in cardiac myocytes. This damage is mediated by the oxidation of proteins and lipids through the modification of genomic and cellular structures [11].…”

Section: Introductionmentioning

confidence: 99%

The role of p53, bax, bcl2, and 8-OHdG in human acute myocardial infarction

et al. 2010

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Apoptosis is implicated in unfavorable remodeling of the left ventricle during acute myocardial infarction (AMI). Both DNA damage and p53 play important roles in regulating apoptosis. Expression patterns of apoptotic regulating genes such as p53, bax, and bcl-2 highlight the importance of inhibiting ventricle remodeling and subsequent injuries. In the present study, serum levels of p53 and 8-hydroxy-2-deoxyguanosine (8-OHdG) as well as p53, bax, and bcl-2 expression were examined after the onset of AMI in Iranian patients. Serum levels of p53 and 8-OHdG were measured by enzyme-linked immunosorbent assay (ELISA) and the presence of p53 protein and mRNA expression of p53, bax, and bcl-2 were analyzed by Western blotting and real time RT-PCR methods respectively. In patients presenting with AMI, serum levels of p53 and 8-OHdG were increased in comparison to healthy controls. Likewise, transcripts of p53 and bax were also elevated in patients while bcl-2 was decreased. Collectively, our data suggest the novel use of p53 and 8-OHdG as markers of apoptosis and DNA damage following AMI. Our results also revealed that apoptosis occurs in concert with an up-regulation of p53 and bax and a down-regulation of bcl-2 which may suggest a possible therapeutic intervention in patients recovering from AMI.© Versita Sp. z o.o.

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Effect of β-Blockers on Free Radical–Induced Cardiac Contractile Dysfunction

Cited by 119 publications

References 38 publications

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange

The role of p53, bax, bcl2, and 8-OHdG in human acute myocardial infarction

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Effect of β-Blockers on Free Radical–Induced Cardiac Contractile Dysfunction

Cited by 119 publications

References 38 publications

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium

Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na + -Ca 2+ Exchange

The role of p53, bax, bcl2, and 8-OHdG in human acute myocardial infarction

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Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na ⁺ -Ca ²⁺ Exchange