期刊
CARDIOVASCULAR RESEARCH
卷 78, 期 1, 页码 79-89出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn001
关键词
PPAR alpha; pressure-overload; hypertrophy; metabolism; fibrosis; inflammation
Aims Peroxisome protiferator-activated receptor-alpha (PPAR alpha) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPAR alpha modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPAR alpha aggravates the cardiac hypertrophic response to pressure overload. Methods and results Male PPAR alpha(-/-) and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (W) watt thickness in PPAR alpha(-/-) than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPAR alpha(-/-) mice. Moreover, after TAC mRNA levels of hypertrophic (atrial. natriuretic factor, alpha-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interteukin-6, tumour necrosis factor-alpha, cycto-oxygenase-2) marker genes were higher in PPAR alpha(-/-) than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyt-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPAR alpha(-/-) mice, but were not further compromised by TAC. Conclusion The present findings show that the absence of PPAR alpha results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPAR alpha exerts salutary effects during cardiac hypertrophy.
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