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

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 ß (TGFß)-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 TGFß- 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.

Human papillomavirus and chlamydia trachomatis infections in rheumatoid arthritis under anti-TNF therapy: an observational study.

The objective of this study was to evaluate human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections in RA patients pre- and post-TNF blocker. Fifty female RA patients (ACR criteria), who were eligible to anti-TNF therapy [n = 50 at baseline (BL) and n = 45 after 6 months of treatment (6 M)], and 50 age-matched healthy controls were prospectively enrolled. They were assessed for demographic data, gynecologic, sexual, cervical cytology and histological evaluations, disease parameters and current treatment. HPV DNA and CT DNA testing in cervical specimens were done using Hybrid Capture II assays. At BL, the median current age of RA patients and controls was 49 (18-74) versus 49 (18-74) years, p = 1.0. A trend of lower frequency of HPV infection was observed in AR patients pre-anti-TNF compared with controls (14 vs. 30%, p = 0.054). Further evaluation of AR patients with and without HPV infection before anti-TNF therapy showed that the former group had higher frequency of sexual intercourses (100 vs. 48%, p = 0.014), higher median number of sexual partners [1 (1-1) vs. 0 (0-1), p = 0.032] and higher frequency of abnormal cervical cytology (43 vs. 7%, p = 0.029). Current age, disease duration, disease parameters and treatments were alike in both groups (p > 0.05). At 6 M after TNF blockage, HPV infection remained unchanged in five patients, whereas two became negative and one additional patient turned out to be positive (p = 1.0). CT infection was uniformly negative in RA patients pre- and post-TNF blockage and in controls. Anti-TNF does not seem to increase short-term risk of exacerbation and/or progression of HPV and CT infections in RA patients.