t0901317 and Cardiomegaly

To investigate the role of liver X receptors (LXRs) on endothelin-1 (ET-1) induced murine HL-1 cardiomyocytes hypertrophy.. Cultured murine HL-1 cardiomyocytes were divided into four experiment groups: (1) CONTROL GROUP:treated with DMSO; (2) T0901317 group:treated with LXRs agonist T0901317 (1 µmol/L); (3) ET-1 group:treated with ET-1 (1 nmol/L); (4) T0901317 + ET-1 group:treated with T0901317 (1 µmol/L) for 8 hours, then treated with ET-1 (1 nmol/L). Twenty-four hours later, immunofluorescent staining was performed on HL-1 cells, the surface area of HL-1 cells was analyzed with NIH Image J software, and the synthetic rate of protein in HL-1 cells was detected by (3)H-leucine incorporation. The mRNA level of atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MyHC) was measured by quantitative realtime PCR. The effect of T0901317 on mRNA expression of ANP was also detected after LXRs gene silencing.. The surface area of HL-1 cells, mRNA expression of ANP and β-MyHC, and (3)H-leucine incorporation in ET-1 group were 2.00 ± 0.29, 1.98 ± 0.47, 2.13 ± 0.39 and 1.79 ± 0.17, respectively, which were significantly higher than those of control group (1.00 ± 0.26, 1.00 ± 0.21, 1.00 ± 0.31 and 1.00 ± 0.03, respectively, all P < 0.05). Compared with ET-1 group, the surface area of HL-1 cells, mRNA expression of ANP and β-MyHC, and (3)H-leucine incorporation were significantly decreased in T0901317 + ET-1 group (1.24 ± 0.25, 1.19 ± 0.21, 1.48 ± 0.27 and 1.15 ± 0.11, respectively, all P < 0.05). After inhibition of LXRα/β expression in HL-1 cardiomyocytes using the specific siRNAs, the mRNA expression of ANP in T0901317 + ET-1 group was 1.78 ± 0.05, which was similar as that in ET-1 group (1.94 ± 0.17, P > 0.05).. T0901317, an agonist of LXRs, could inhibit ET-1 induced cardiac hypertrophy in vitro, and LXR ligand-mediated inhibition on ANP mRNA expression by T0901317 is receptor dependent.

Topics: Animals; Cardiomegaly; Cell Line; Endothelin-1; Hydrocarbons, Fluorinated; Liver X Receptors; Mice; Myocytes, Cardiac; Orphan Nuclear Receptors; Signal Transduction; Sulfonamides

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.. 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.. 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.

Topics: Adenoviridae; Angiotensin II; Animals; Cardiomegaly; Cells, Cultured; DNA-Binding Proteins; Hydrocarbons, Fluorinated; Inflammation; Lipopolysaccharides; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Sulfonamides; Toll-Like Receptor 4