Activation of the peroxisome proliferator-activated receptor alpha protects against myocardial ischaemic injury and improves endothelial vasodilatation.
BACKGROUND
The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To evaluate the possible protective role of PPARalpha on cardiovascular function, the effect of the PPARalpha agonist, fenofibrate was assessed with respect to ischaemia/reperfusion injury and endothelial function in mice.


RESULTS
Fenofibrate treatment reduces myocardial infarction size and improves post-ischaemic contractile dysfunction. Hearts from PPARalpha null mice exhibit increased susceptibility to ischaemic damages and were refractory to protection by fenofibrate treatment suggesting that the beneficial effects of fenofibrate were mediated via PPARalpha. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. A decreased inhibitory effect of reactive oxygen species in the vessel wall accounts for enhanced endothelial vasodilatation. However, the latter cannot be explained by an increase in nitric oxide synthase expression nor by an increase sensitivity of the arteries to nitric oxide.


CONCLUSIONS
Altogether the present data suggest that fenofibrate exerts cardioprotective effect against ischaemia and improves nitric oxide-mediated response probably by enhancing antioxidant capacity of the vessel wall. These data underscore new therapeutic perspectives for PPARalpha agonists in ischaemic myocardial injury and in cardiovascular diseases associated with endothelial dysfunction.
Tabernero
Antonia
A
Laboratoire de Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, UMR-CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, 74 route du Rhin BP 24, 67401 Illkirch, France. antonia_nancy@hotmail.com
Schoonjans
Kristina
K
Jesel
Laurence
L
Carpusca
Irina
I
Auwerx
Johan
J
Andriantsitohaina
Ramaroson
R
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D011345:Fenofibrate / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011345:Fenofibrate