gw9662 and Hypertrophy

To investigate the potential effect of curcumin on cardiomyocyte hypertrophy and a possible mechanism involving the PPARγ/Akt/NO signaling pathway in diabetes.. The cardiomyocyte hypertrophy induced by high glucose (25.5mmol/L) and insulin (0.1μmol/L) (HGI) and the antihypertrophic effect of curcumin were evaluated in primary culture by measuring the cell surface area, protein content and atrial natriuretic factor (ANF) mRNA expression. The mRNA and protein expressions were assayed by reverse transcription PCR and Western blotting, whereas the NO concentration and endothelial NO synthase (eNOS) activity were determined using nitrate reduction and ELISA methods, respectively.. The cardiomyocyte hypertrophy induced by HGI was characterized by increasing ANF mRNA expression, total protein content, and cell surface area, with downregulated mRNA and protein expressions of both PPARγ and Akt, which paralleled the declining eNOS mRNA expression, eNOS content, and NO concentration. The effects of HGI were inhibited by curcumin (1, 3, 10μmol/L) in a concentration-dependent manner. GW9662 (10μmol/L), a selective PPARγ antagonist, could abolish the effects of curcumin. LY294002 (20μmol/L), an Akt blocker, and N(G)-nitro-l-arginine-methyl ester (100μmol/L), a NOS inhibitor, could also diminish the effects of curcumin.. The results suggested that curcumin supplementation can improve HGI-induced cardiomyocytes hypertrophy in vitro through the activation of PPARγ/Akt/NO signaling pathway.

Topics: Anilides; Animals; Atrial Natriuretic Factor; Cells, Cultured; Chromones; Curcumin; Glucose; Hypertrophy; Insulin; Morpholines; Myocytes, Cardiac; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction

Telmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) γ, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo.. Nine-week-old male db/db mice were fed a 60% high-fat diet, with orally administrated either vehicle (carboxymethyl-cellulose, CMC), 5 mg/kg telmisartan, or 5 mg/kg telmisartan and 1 mg/kg GW9662, a selective irreversible antagonist of PPARγ, for 5 weeks. Effects of telmisartan on Sirt1 mRNA, AMPK phosphorylation, and NAD+/NADH ratio were determined in C2C12 cultured myocytes.. Telmisartan treatment improved insulin sensitivity in obese db/db mice fed a high-fat diet and led to reduction in the size of hypertrophic pancreatic islets in these mice. Moreover, in vitro treatment with telmisartan led to increased expression of Sirt1 mRNA in C2C12 skeletal muscle cells; the increase in Sirt1 mRNA in telmisartan-treated C2C12 myoblasts occurred concomitantly with an increase in AMPK phosphorylation, an increase in NAD+/NADH ratio, and increases in the mRNA levels of PGC1α, FATP1, ACO, and GLUT4.. Our results indicate that telmisartan acts through a PPARγ-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.

Topics: Adipocytes; Administration, Oral; AMP-Activated Protein Kinases; Angiotensin II Type 1 Receptor Blockers; Anilides; Animals; Benzimidazoles; Benzoates; Cell Line; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fatty Acid Transport Proteins; Glucose Transporter Type 4; Hypertrophy; Insulin; Islets of Langerhans; Male; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; NAD; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; PPAR gamma; RNA, Messenger; Signal Transduction; Sirtuin 1; Telmisartan; Time Factors; Trans-Activators; Transcription Factors