Liver X receptors are negative regulators of cardiac hypertrophy via suppressing NF-kappaB signalling.
OBJECTIVE
Nuclear factor-kappaB (NF-kappaB) plays a critical role in cell growth and inflammation during the progression of cardiac hypertrophy and heart failure. Several members of nuclear receptor superfamily, including liver X receptors (LXRalpha and LXRbeta), have been shown to suppress inflammatory responses, but little is known about their effects in cardiomyocytes.


RESULTS
We investigated LXR expression patterns in pressure overload-induced hypertrophic hearts and the hypertrophic growth of the LXRalpha-deficient hearts from mice (C57/B6) in response to pressure overload. The underlying mechanisms were also explored using cultured myocytes. We found that cardiac expression of LXRalpha was upregulated in pressure overload-induced left ventricular hypertrophy in mice. Transverse aorta coarctation-induced left ventricular hypertrophy was exacerbated in LXRalpha-null mice relative to control mice. A synthetic LXR ligand, T1317, suppressed cardiomyocyte hypertrophy in response to angiotensin II and lipopolysaccharide treatments. In addition, LXR activation suppressed NF-kappaB signalling and the expression of associated inflammatory factors. Overexpression of constitutively active LXRalpha and beta in cultured myocytes suppressed NF-kappaB activity.


CONCLUSIONS
LXRs are negative regulators of cardiac growth and inflammation via suppressing NF-kappaB signalling in cardiomyocytes. This should provide new insights into novel therapeutic targets for treating cardiac hypertrophy and heart failure.
Wu
Sijie
S
Department of Nutrition Sciences, University of Alabama at Birmingham, Webb 435, 1675 University Boulevard, Birmingham, AL 35242, USA.
Yin
Ran
R
Ernest
Rick
R
Li
Yuquan
Y
Zhelyabovska
Olga
O
Luo
Jinwen
J
Yang
Yifeng
Y
Yang
Qinglin
Q
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000633:toxicity; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000804:Angiotensin II; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C493487:Tlr4 protein, mouse