title: Cardiac hypertrophy is enhanced in PPAR alpha-/- mice in response to chronic pressure overload.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-alpha (PPARalpha) 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 PPARalpha modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARalpha aggravates the cardiac hypertrophic response to pressure overload.
  
  
  RESULTS
  Male PPARalpha-/- 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 (LV) wall thickness in PPARalpha-/- 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 PPARalpha-/- mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, alpha-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-alpha, cyclo-oxygenase-2) marker genes were higher in PPARalpha-/- than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPARalpha-/- mice, but were not further compromised by TAC.
  
  
  CONCLUSIONS
  The present findings show that the absence of PPARalpha 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 PPARalpha exerts salutary effects during cardiac hypertrophy.
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands.
authors.forename: Pascal J H
authors.initials: PJ
authors.lastname: Smeets
authors.forename: Birgit E J
authors.initials: BE
authors.lastname: Teunissen
authors.forename: Peter H M
authors.initials: PH
authors.lastname: Willemsen
authors.forename: Frans A
authors.initials: FA
authors.lastname: van Nieuwenhoven
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Brouns
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jack P M
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Ger J
authors.initials: GJ
authors.lastname: van der Vusse
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013318:Stroke Volume; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D000199:Actins; D024042:Collagen Type I; D015850:Interleukin-6; D047493:PPAR alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009320:Atrial Natriuretic Factor; D015094:3-Hydroxyacyl CoA Dehydrogenases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D003066:Coenzyme A Ligases