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The liver X receptor agonist AZ876 protects against pathological cardiac hypertrophy and fibrosis without lipogenic side effects
Author(s) -
Can Megan V.,
Yu Hongjuan,
Candido Wellington M.,
Dokter Martin M.,
Lindstedt EvaLotte,
Silljé Herman H.W.,
van Gilst Wiek H.,
de Boer Rudolf A.
Publication year - 2015
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.243
Subject(s) - cardiac fibrosis , endocrinology , medicine , liver x receptor , fibrosis , pressure overload , agonist , muscle hypertrophy , heart failure , phenylephrine , angiotensin ii , receptor , blood pressure , biology , nuclear receptor , cardiac hypertrophy , transcription factor , biochemistry , gene
Aims Liver X receptors ( LXRs ) transcriptionally regulate inflammation, metabolism, and immunity. Synthetic LXR agonists have been evaluated for their efficacy in the cardiovascular system; however, they elicit prolipogenic side effects which substantially limit their therapeutic use. AZ876 is a novel high‐affinity LXR agonist. Herein, we aimed to determine the cardioprotective potential of LXR activation with AZ876 . Methods and results Cardiac hypertrophy was induced in C57Bl6 /J mice via transverse aortic constriction ( TAC ) for 6 weeks. During this period, mice received chow supplemented or not with AZ876 (20 µmol/kg/day). In murine hearts, LXRα protein expression was up‐regulated ∼7‐fold in response to TAC . LXR activation with AZ876 attenuated this increase, and significantly reduced TAC ‐induced increases in heart weight, myocardial fibrosis, and cardiac dysfunction without affecting blood pressure. At the molecular level, AZ876 suppressed up‐regulation of hypertrophy‐ and fibrosis‐related genes, and further inhibited prohypertrophic and profibrotic transforming growth factor β ( TGFβ )–Smad2/3 signalling. In isolated cardiac myocytes and fibroblasts, immunocytochemistry confirmed nuclear expression of LXRα in both these cell types. In cardiomyocytes, phenylephrine‐stimulated cellular hypertrophy was significantly decreased in AZ876 ‐treated cells. In cardiac fibroblasts, AZ876 prevented TGFβ ‐ and angiotensin II ‐induced fibroblast collagen synthesis, and inhibited up‐regulation of the myofibroblastic marker, α‐smooth muscle actin. Plasma triglycerides and liver weight were unaltered following AZ876 treatment. Conclusion AZ876 activation of LXR protects from adverse cardiac remodelling in pathological pressure overload, independently of blood pressure. LXR may thus represent a putative molecular target for antihypertrophic and antifibrotic therapies in heart failure prevention.