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Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-α KO mouse

Abstract : Guellich A, Damy T, Conti M, Claes V, Samuel JL, Pineau T, Lecarpentier Y, Coirault C. Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-␣ KO mouse.oxisome proliferator-activated receptor (PPAR)-␣ deletion induces a profound decrease in MnSOD activity, leading to oxidative stress and left ventricular (LV) dysfunction. We tested the hypothesis that treatment of PPAR-␣ knockout (KO) mice with the SOD mimetic tempol prevents the heart from pathological remodelling and preserves LV function. Twenty PPAR-␣ KO mice and 20 age-matched wild-type mice were randomly treated for 8 wk with vehicle or tempol in the drinking water. LV contractile parameters were determined both in vivo using echocardiography and ex vivo using papillary muscle mechanics. Translational and posttranslational modifications of myo-sin heavy chain protein as well as the expression and activity of major antioxidant enzymes were measured. Tempol treatment did not affect LV function in wild-type mice; however, in PPAR-␣ KO mice, tempol prevented the decrease in LV ejection fraction and restored the contractile parameters of papillary muscle, including maximum shortening velocity, maximum extent of shortening, and total tension. Moreover, compared with untreated PPAR-␣ KO mice, myosin heavy chain tyrosine nitration and anion superoxide production were markedly reduced in PPAR-␣ KO mice after treatment. Tempol also significantly increased glutathione peroxidase and glutathione reduc-tase activities (ϳ 50%) in PPAR-␣ KO mice. In conclusion, these findings demonstrate that treatment with the SOD mimetic tempol can prevent cardiac dysfunction in PPAR-␣ KO mice by reducing the oxidation of contractile proteins. In addition, we show that the beneficial effects of tempol in PPAR-␣ KO mice involve activation of the glutathione peroxidase/glutathione reductase system.
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Aziz Guellich, Thibaud Damy, Marc Conti, Victor Claes, Jane-Lise Samuel, et al.. Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-α KO mouse. AJP - Heart and Circulatory Physiology, American Physiological Society, 2013, 304 (11), pp.H1505-H1512. ⟨10.1152/ajpheart.00669.2012⟩. ⟨inserm-02426477⟩



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