Role of oxidative stress in cardiac dysfunction of PPARα^−/−mice

Abstract

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.

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

“…This explanation would be compatible with the higher coronary flow of PPAR␣ null mouse hearts at the higher preload. Incidentally, a recent study by Guellich et al (15) demonstrated oxidative damage to contractile proteins, specifically tyrosine nitration of myosin, in these hearts, suggesting an increased production of free radicals and nitric oxide. This may also offer an explanation for the change in activity of NADP ϩ -isocitrate dehydrogenase, an enzyme that is affected by oxidative stress-related molecules.…”

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

“…Previous studies found that cardiac PPARa deficiency led to significant decrease of LV SOD2 expression (8). Further studies demonstrated that the absence of PPARa results in a more pronounced hypertrophic growth response and signs of functional deterioration (28).…”

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

“…Each PPAR typic changes. In a study reporting cardiac contractile dysfunction in PPARα null mice, a mechanism of oxidative damage in sarcomere proteins and lipid peroxidation was proposed based on the observation that a significant decrease of SOD2 protein and the corresponding activity with no change of other antioxidant enzymes such as Cu/ZnSOD (SOD1), catalase, and glutathione peroxidase (GPx) was reported [46] . It is not clear if the repression of SOD2 protein level and activity also occurred at the transcript level.…”