Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Background-Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the nuclear receptor superfamily. It has been reported that the thiazolidinediones, which are antidiabetic agents and high-affinity ligands for PPAR␥, regulate growth of vascular cells. In the present study, we examined the role of PPAR␥ in angiotensin II (Ang II)-induced hypertrophy of neonatal rat cardiac myocytes and in pressure overload-induced cardiac hypertrophy of mice. Methods and Results-Treatment of cultured cardiac myocytes with PPAR␥ ligands such as troglitazone, pioglitazone, and rosiglitazone inhibited Ang II-induced upregulation of skeletal ␣-actin and atrial natriuretic peptide genes and an increase in cell surface area. Treatment of mice with a PPAR␥ ligand, pioglitazone, inhibited pressure overload-induced increases in the heart weight-to-body weight ratio, wall thickness, and myocyte diameter in wild-type mice and an increase in the heart weight-to-body weight ratio in heterozygous PPAR␥-deficient mice. In contrast, pressure overload-induced increases in the heart weight-to-body weight ratio and wall thickness were more prominent in heterozygous PPAR␥-deficient mice than in wild-type mice. Conclusions-These results suggest that the PPAR␥-dependent pathway is critically involved in the inhibition of cardiac hypertrophy.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Recently, PPAR activators have been shown to inhibit the production of proinflammatory cytokines in macrophages or vascular smooth muscle cells. It has been reported that tumor necrosis factor-alpha (TNF-alpha) expression is elevated in the failing heart and that TNF-alpha has a negative inotropic effect on cardiac myocytes. Therefore, we examined the effects of PPARalpha and PPARgamma activators on expression of TNF-alpha in neonatal rat cardiac myocytes. Northern blot analysis revealed expression of PPARalpha and PPARgamma mRNA in cardiac myocytes. Immunofluorescent staining demonstrated that both PPARalpha and PPARgamma were expressed in the nuclei of cells. When cardiac myocytes were transfected with PPAR responsive element (PPRE)-luciferase reporter plasmid, both PPARalpha and PPARgamma activators increased the promoter activity. Cardiomyocytes were stimulated with lipopolysaccharide (LPS), and the levels of TNF-alpha in the medium were measured by ELISA. After exposure to LPS, the levels of TNF-alpha significantly increased. However, pretreatment of myocytes with PPARalpha or PPARgamma activators decreased LPS-induced expression of TNF-alpha in the medium. Both PPARalpha and PPARgamma activators also inhibited LPS-induced increase in TNF-alpha mRNA in myocytes. In addition, electrophoretic mobility shift assays demonstrated that PPAR activators reduced LPS-induced nuclear factor-kappaB activation. These results suggest that both PPARalpha and PPARgamma activators inhibit cardiac expression of TNF-alpha in part by antagonizing nuclear factor-kappaB activity and that treatment with PPAR activators may lead to improvement in congestive heart failure.