Title
Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-<tex>$\alpha$</tex> KO mouse
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Bethesda, Md ,
Subject
Human medicine
Source (journal)
American journal of physiology: heart and circulatory physiology. - Bethesda, Md
Volume/pages
304(2013) :11 , p. 505-512
ISSN
0363-6135
0363-6135
ISI
000319808200010
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Peroxisome proliferator-activated receptor (PPAR)-alpha 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-alpha knockout (KO) mice with the SOD mimetic tempol prevents the heart from pathological remodelling and preserves LV function. Twenty PPAR-alpha 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 myosin 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-alpha 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-alpha KO mice, myosin heavy chain tyrosine nitration and anion superoxide production were markedly reduced in PPAR-alpha KO mice after treatment. Tempol also significantly increased glutathione peroxidase and glutathione reductase activities (similar to 50%) in PPAR-alpha KO mice. In conclusion, these findings demonstrate that treatment with the SOD mimetic tempol can prevent cardiac dysfunction in PPAR-alpha KO mice by reducing the oxidation of contractile proteins. In addition, we show that the beneficial effects of tempol in PPAR-alpha KO mice involve activation of the glutathione peroxidase/glutathione reductase system.
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