gw0742 and Cardiomegaly

Peroxisome proliferator-activated receptor δ (PPARδ), the predominant PPAR subtype in the heart, is known to regulate cardiac function. PPARδ activation may inhibit cardiac hypertrophy in H9c2 cells while the potential mechanism has not been elucidated. Then, H9c2 cells incubated with high glucose to induce hypertrophy were used to investigate using GW0742 to activate PPARδ. The fluorescence assays were applied to determine the changes in cell size, cellular calcium levels, and free radicals. Western blot analyses for hypertrophic signals and assays of messenger RNA (mRNA) levels for hypertrophic biomarkers were performed. In H9c2 cells, GW0742 inhibited cardiac hypertrophy. In addition, increases in cellular calcium and hypertrophic signals, including calcineurin and nuclear factor of activated T-cells, were reduced by GW0742. This reduction was parallel to the decrease in the mRNA levels of biomarkers, such as brain/B-type natriuretic peptides and β-myosin heavy chain. These effects of GW0742 were dose-dependently inhibited by GSK0660 indicating an activation of PPARδ by GW0742 to alleviate cardiac hypertrophy. Moreover, free radicals produced by hyperglycemia were also markedly inhibited by GW0742 and were later reversed by GSK0660. GW0742 promoted the expression of thioredoxin, an antioxidant enzyme. Direct inhibition of reactive oxygen species by GW0742 was also identified in the oxidant potassium bromate stimulated H9c2 cells. Taken together, these findings suggest that PPARδ agonists can inhibit free radicals, resulting in lower cellular calcium for reduction of hypertrophic signaling to alleviate cardiac hypertrophy in H9c2 cells. Therefore, PPARδ activation can be used to develop agent(s) for treating cardiac hypertrophy.

Topics: Animals; Blotting, Western; Calcium; Cardiomegaly; Cell Line; Free Radicals; Hyperglycemia; Rats; Reactive Oxygen Species; Sulfones; Thiazoles; Thiophenes

Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension.. Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model.. These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

Topics: Administration, Oral; Animals; Cardiomegaly; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Transgenic; PPAR delta; PPAR-beta; Rats; Rats, Wistar; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Thiazoles

Agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (gamma) exert anti-proliferative and anti-inflammatory effects that led to the testing of these drugs in experimental cardiac hypertrophy. However, the effect of PPAR beta/delta (beta/delta) agonists in hypertrophy is not yet known. In this paper, an experiment was conducted to explore whether PPARbeta/delta activation has an effect on cardiac hypertrophy. An in vitro cardiomyocyte hypertrophy from neonatal rats was induced with Angiotensin II (Ang II1micromol x L(-1)) stimulation. For the examination of PPAR beta/delta effect, the cultured rat cardiac myocytes were pretreated with GW0742 (10 micromol.L(-1)), an agonist of PPARbeta/delta, for 48h before Ang II stimulation. The following parameters in the cultured cells were determined: surface areas of myocytes were measured by the NIH Image Software; (3)H-leucine incorporation into myocytes was counted by liquid scintillometer; mRNA expression of PPARbeta/delta, ANP, BNP, MMP9, MMP2, and IL-1beta was detected by RT-PCR; PPARbeta/delta protein expression was evaluated with immunofluorescence staining; GW0742 could ameliorate Ang II-induced cardiomyocyte hypertrophy, as indicated by its inhibitory effects on the surface area of myocytes, and ANP and BNP mRNA expressions in myocytes and (3)H-leucine incorporation into myocytes. Meanwhile, GW0742 pretreatment exerted inhibition on mRNA expression augmentation of such cytokines as MMP9, MMP2, and IL-1beta in hypertrophic myocytes. In addition, the down-regulated expression of PPARbeta/delta mRNA and protein in hypertrophic myocytes was also significantly reversed by GW0742. We demonstrate for the first time that GW0742 exerts a beneficial effect on Ang II-induced cardiac hypertrophy and the relation to inflammation response.

Topics: Angiotensin II; Animals; Cardiomegaly; Cell Membrane; Cells, Cultured; Cytokines; Down-Regulation; Fluorescent Antibody Technique; In Vitro Techniques; Leucine; Myocytes, Cardiac; PPAR delta; PPAR-beta; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staining and Labeling; Thiazoles