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-/- Mice
1 CRCIL U689, INSERM, France
2 AP-HP, France
3 CRCIL U689, INSERM, France; Paris XI, University, France
4 Biochemistry, CHU Bicètre, Paris, France
5 University of Antwerp, Antwerp, Belgium
6 CRCIL U689, INSERM, France; University Paris VII, Paris, France
7 AP-HP, Le Kremlin-Bicetre, France; Paris XI, University, France
8 AP-HP, France; Paris XI, University, France
9 Laboratoire de Pharmacologie et Toxicologie, INRA, France
10 CRCIL U689, INSERM, Paris, France; University Paris VII, Paris, France
* To whom correspondence should be addressed. E-mail: coirault{at}larib.inserm.fr.
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 blotting and immunolabeling. Radical scavenging capacity was analyzed by measuring protein levels and/or activities of the main antioxidant enzymes including catalase, glutathione peroxidase, manganese and copper-zinc superoxide dismutases. Echocardiographic left ventricular fractional shortening in PPAR-/- was 16% lower than in wild-type. Ex vivo left ventricular papillary muscle exhibited reduced shortening velocity and isometric tension (3- and 2-fold 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 2-fold higher in PPAR-/- and 4-hydroxy-2-nonenal protein-adducts were 3-fold 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.
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