title: Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy in vivo.
abstract: OBJECTIVE
  Liver X receptor (LXR) is a nuclear receptor regulating cholesterol metabolism. Liver X receptor has also been shown to exert anti-proliferative and anti-inflammatory properties. In this study, we evaluated the effect of LXR activation on cardiac hypertrophy in vitro and in vivo.
  
  
  RESULTS
  Treatment with the synthetic LXR agonist T0901317 (T09) attenuated the hypertrophic response of cultured cardiomyocytes to endothelin-1 almost to control levels. siRNA interference showed that this effect was indeed LXR specific. To corroborate these findings in vivo, abdominal aortic constriction (AC) was used as a pressure overload model to induce cardiac hypertrophy in wild-type and LXR-α-deficient (LXR-α(-/-)) mice. In wild-type mice, T09 treatment resulted in a decrease of cardiac wall thickening 4 and 7 weeks after AC. Also, after 7 weeks of AC, mean arterial blood pressure and left ventricular weight/body weight (LVW/BW) ratios were decreased in T09 treated mice. These effects were not observed in LXR-α(-/-) mice, indicating that the beneficial effect of LXR activation on cardiac hypertrophy is attributable to the LXR-α isoform. T09 induced robust cardiac expression of metabolic genes which are downstream of LXR-α, such as SREBP-1c, ABCA1, and ABCG1.
  
  
  CONCLUSIONS
  Together these results indicate that LXR exerts salutary effects in cardiac hypertrophy, possibly via metabolic remodelling.
authors.affiliation: Department of Experimental Cardiology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: Kuipers
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Inge
authors.initials: I
authors.lastname: Vreeswijk-Baudoin
authors.forename: Johan
authors.initials: J
authors.lastname: Koster
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D019332:Endothelin-1; D006352:Heart Ventricles / Q000187:drug effects*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy*; D066298:In Vitro Techniques; D000071518:Liver X Receptors; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects*; D057093:Orphan Nuclear Receptors / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology*; D014463:Ultrasonography; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D019332:Endothelin-1; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D013449:Sulfonamides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides