Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy in vivo.
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.
Kuipers
Irma
I
Department of Experimental Cardiology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
Li
Jiang
J
Vreeswijk-Baudoin
Inge
I
Koster
Johan
J
van der Harst
Pim
P
Silljé
Herman H W
HH
Kuipers
Folkert
F
van Veldhuisen
Dirk J
DJ
van Gilst
Wiek H
WH
de Boer
Rudolf A
RA
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
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