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Role of oxidative stress in cardiac dysfunction of PPAR^–/– mice

¹Institut National de la Santé et de la Recherche Médicale (INSERM) U689, Centre de Recherche Cardiovasculaire INSERM Lariboisière, Paris, France; Université Paris VII, Paris, France; ²INSERM U660; ⁴Faculté de Médecine Paris XII, Créteil Cedex France, ³Services d'Explorations Cardio-Respiratoires; ⁴de Biochimie et ⁵d'Anatomie-Pathologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris; Université Paris XI, Le Kremlin-Bicêtre, France; ⁶University of Antwerp, Centrum Technologie voor Gehandicapte Persone, Antwerp, Belgium; and ⁷Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique, Toulouse, France

Submitted 10 January 2007 ; accepted in final form 15 March 2007

This study was designed to determine the effects of PPAR lack on cardiac mechanical performance and to identify potential intracellular mechanisms linking PPAR pathway deficiency to cardiac contractile dysfunction. Echocardiography, ex vivo papillary muscle assays, and in vitro motility assays were used to assess global, intrinsic ventricular muscle performance and myosin mechanical properties, respectively, in PPAR^–/– and age-matched wild-type mice. Three-nitrotyrosine formation and 4-hydroxy-2-nonenal protein-adducts, both markers of oxidative damage, were analyzed by Western blot analysis and immunolabeling. Radical scavenging capacity was analyzed by measuring protein levels and/or activities of the main antioxidant enzymes, including catalase, glutathione peroxidase, and manganese and copper-zinc superoxide dismutases. Echocardiographic left ventricular fractional shortening in PPAR^–/– was 16% lower than that in wild-type. Ex vivo left ventricular papillary muscle exhibited reduced shortening velocity and isometric tension (three- and twofold, respectively). In vitro myosin-based velocity was 20% slower in PPAR^–/–, indicating that myosin itself was involved in the contractile dysfunction. Staining of 3-nitrotyrosine was more pronounced in PPAR^–/–, and myosin heavy chain was the main nitrated protein. Formation of 3-nitrotyrosine myosin heavy chain was twofold higher in PPAR^–/– and 4-hydroxy-2-nonenal protein-adducts were threefold higher. The expression and activity of manganese superoxide dismutase were respectively 33% and 50% lower in PPAR^–/–, with no changes in copper-zinc superoxide dismutase, catalase, or glutathione peroxidase. These findings demonstrate that PPAR pathway deficiency impairs cardiac function and also identify oxidative damage to myosin as a link between PPAR deficiency and contractile dysfunction.

contractility; metabolism; myosin; cardiac failure

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