The liver X receptor agonist AZ876 protects against pathological cardiac hypertrophy and fibrosis without lipogenic side effects

Abstract

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.

Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

“…Cannon et al . also reported that an LXR-α agonist significantly improves transverse aortic constriction-induced cardiac dysfunction and cardiac fibrosis in vivo 29. Furthermore, Ang II and Ang(1-7), two important elements of the RAS, inhibit and activate LXR-α expression, respectively3031.…”

Mimicking Cardiac Fibrosis in a Dish: Fibroblast Density Rather than Collagen Density Weakens Cardiomyocyte Function

“…Although multiple mouse models for cardiac disease are available in this study, the mdx and TAC model were chosen because the origin and development of fibrosis in these two models is different. Secondly, both mouse models are frequently described in literature and often used to test anti-fibrotic therapies [12–16]. The mdx mouse was chosen as a model of genetic cardiac disease [17, 18], while a mouse model with transverse aortic constriction (TAC) was chosen to represent acquired heart disease [19].…”

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

“…At the cellular level, LXRs have been shown to attenuate hypertrophy in neonatal cardiomyocyte via improved metabolic substrate use, downregulation of collagen synthesis, and profibrotic gene expression in cardiac fibroblasts55; and they have reduced apoptosis by inhibition of caspase‐3 protein expression 56. Analysis of the gene profiling data revealed that the expression of cholesterol 7α‐hydroxylase ( Cyp7a ), a target gene activated by LxRα,57 was significantly increased by 3.3‐fold in INSL6‐treated mouse hearts compared with nontreated mouse hearts subjected to isoproterenol insult.…”