Role of oxidative stress in cardiac dysfunction of PPARalpha-/- mice.
This study was designed to determine the effects of PPARalpha lack on cardiac mechanical performance and to identify potential intracellular mechanisms linking PPARalpha 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 PPARalpha(-/-) 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 PPARalpha(-/-) 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 approximately 20% slower in PPARalpha(-/-), indicating that myosin itself was involved in the contractile dysfunction. Staining of 3-nitrotyrosine was more pronounced in PPARalpha(-/-), and myosin heavy chain was the main nitrated protein. Formation of 3-nitrotyrosine myosin heavy chain was twofold higher in PPARalpha(-/-) 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 PPARalpha(-/-), with no changes in copper-zinc superoxide dismutase, catalase, or glutathione peroxidase. These findings demonstrate that PPARalpha pathway deficiency impairs cardiac function and also identify oxidative damage to myosin as a link between PPARalpha deficiency and contractile dysfunction.
Guellich
Aziz
A
INSERM U689, Centre de Recherche Cardiovasculaire INSERM Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France.
Damy
Thibaud
T
Lecarpentier
Yves
Y
Conti
Marc
M
Claes
Victor
V
Samuel
Jane-Lyse
JL
Quillard
Jeanine
J
Hébert
Jean-Louis
JL
Pineau
Thierry
T
Coirault
Catherine
C
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009218:Myosins / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
D016207:Cytokines; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D009218:Myosins