Dexrazoxane prevents the development of the impaired cardiac phenotype in caveolin-1-disrupted mice.

Abstract

: Caveolin-1-deficient (cav1) mice display a severely diseased cardiac phenotype with systolic and diastolic heart failure. Accumulating evidence supports a causative role of uncoupled endothelial nitric oxide synthase in the development of these abnormalities. Interestingly, a similar molecular mechanism was proposed for anthracycline-induced cardiomyopathy. Currently, dexrazoxane is approved for the prevention of anthracycline-induced cardiomyopathy. Given the molecular similarities between the anthracycline-induced cardiomyopathy and the cardiomyopathy in cav1 mice, we questioned whether dexrazoxane may also prevent the evolution of the cardiac pathologies in cav1 mice. We evaluated dexrazoxane treatment for 6 weeks in cav1 mice and wild-type controls. This study provides the first evidence for a reduced reactive oxygen species formation in the vessels of dexrazoxane-treated cav1 mice. This reduced oxidative stress resulted in a markedly reduced rate of apoptosis, which finally was translated into a significantly improved heart function in dexrazoxane-treated cav1 mice. These hemodynamic improvements were accompanied by significantly lowered proatrial natriuretic peptide levels. Notably, these protective properties of dexrazoxane were not evident in wild-type animals. Taken together, these novel findings indicate that dexrazoxane significantly reduces vascular reactive oxygen species formation cav1. Because this is paralleled by an improved cardiac performance in cav1 mice, our data suggest dexrazoxane as a novel therapeutic strategy in this specific cardiomyopathy.

• Authors: Anne-Katrin Polanski, Annette Ebner, Bernd Ebner, Anja Hofmann, Nadine Steinbronn, Aljoscha Brandt, Mathias Forkmann, Anne-Kathrin Tausche, Henning Morawietz, Ruth H Strasser, Carsten Wunderlich
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 61 Issue 6 Pg. 545-52 (Jun 2013) ISSN: 1533-4023 [Electronic] United States
• PMID: 23474841 (Publication Type: Journal Article)

Chemical References

• Cardiovascular Agents
• Caveolin 1
• Reactive Oxygen Species
• Razoxane
• Atrial Natriuretic Factor
• Nitric Oxide Synthase

Topics

• Animals
• Apoptosis (drug effects)
• Atrial Natriuretic Factor (blood, drug effects)
• Cardiomyopathies (genetics, metabolism, physiopathology, prevention & control)
• Cardiovascular Agents (therapeutic use)
• Caveolin 1 (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase (drug effects, metabolism)
• Phenotype
• Razoxane (therapeutic use)
• Reactive Oxygen Species (metabolism)
• Treatment Outcome
• Ventricular Function, Left (drug effects)