Catalase Mediates The Inhibitory Actions Of Ppar Delta Against Angiotensin Ii-Triggered Hypertrophy In H9c2 Cardiomyocytes

Hypertrophy of myocytes has been implicated in cardiac dysfunctions affecting wall stress and patterns of gene expression. However, molecular targets potentially preventing cardiac hypertrophy have not been fully elucidated. In the present study, we demonstrate that upregulation of catalase by peroxisome proliferator-activated receptor delta (PPAR delta) is involved in the anti-hypertrophic activity of PPAR delta in angiotensin II (Ang II)-treated H9c2 cardiomyocytes. Activation of PPAR delta by a specific ligand GW501516 significantly inhibited Ang II-induced hypertrophy and the generation of reactive oxygen species (ROS) in H9c2 cardiomyocytes. These effects of GW501516 were almost completely abolished in cells stably expressing small hairpin (sh)RNA targeting PPAR delta, indicating that PPAR delta mediates these effects. Significant concentration and time-dependent increases in catalase at both mRNA and protein levels were observed in GW501516-treated H9c2 cardiomyocytes. In addition, GW501516-activated PPAR delta significantly enhanced catalase promoter activity and protein expression, even in the presence of Ang II. GW501516-activated PPAR delta also inhibited the expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which are both marker proteins for hypertrophy. The effects of GW501516 on the expression of ANP and BNP were reversed by 3-amino-1,2,4-triazole (3-AT), a catalase inhibitor. Inhibition or downregulation of catalase by 3-AT or small interfering (si)RNA, respectively, abrogated the effects of PPAR delta on Ang II-induced hypertrophy and ROS generation, indicating that these effects of PPAR delta are mediated through catalase induction. Furthermore, GW501516-activated PPAR delta exerted catalase-dependent inhibitory effects on Ang II-induced hypertrophy by blocking p38 mitogen-activated protein kinase. Taken together, these results indicate that the anti-hypertrophic activity of PPAR delta may be achieved, at least in part, by sequestering ROS through fine-tuning the expression of catalase in cardiomyocytes.