Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes

Background-Peroxisome proliferator-activated receptors (PPARs) are transcri ption factors belonging to the nuclear receptor superfamily. PPAR gamma mRN A is present in cardiac myocytes; however, whether PPAR gamma affects cardi ac hypertrophy remains unknown. Methods and Results-We investigated the effects of PPAR gamma activators on cardiac hypertrophy in neonatal rat cardiac myocytes. Cyclic 4% biaxial me chanical strain caused enlargement of cardiac myocytes (1.3-fold versus con trol, P <0.0001), but the PPAR gamma activators troglitazone and 15-deoxy-D elta (12-14)-prostaglandin J(2) (15d-PGJ(2)) (10 mu mol/L) inhibited this e ffect (troglitazone, -72%, P <0.0005; 15d-PGJ(2), -88%, P <0.0002). Total c ell protein was increased by mechanical strain (control, 164.3 mug/dish; st rain, 265.5, P <0.0002), and this effect was inhibited by troglitazone and 15d-PGJ2 (troglitazone, -61%, P <0.005; 15d-PGJ2, -72%, P <0.001). [H-3]Leu cine uptake was also increased by mechanical strain (1.9-fold versus contro l, P <0.002), and this increase was inhibited by troglitazone and 15d-PGJ(2 ), (troglitazone, -52% at 10 mu moI/L, P <0.01; 15d-PGJ(2), -70% at 10 mu m ol/L, P <0.005). An increase in [H-3]leucine uptake induced by angiotensin II or phenylephrine was significantly inhibited by troglitazone and 15d-PGJ (2). Mechanical strain induced mRNA expression for brain natriuretic peptid e, but PPAR gamma activators inhibited this induction. Furthermore, PPAR ga mma activators inhibited mechanically induced activation of nuclear factor (NF)-kappaB. Pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activat ion, inhibited strain-induced [H-3]leucine uptake (-50% at 100 mu mol/L, P <0.05). Conclusions These results demonstrate that PPAR gamma activators inhibit ca rdiac hypertrophy in cardiac myocytes and suggest that PPAR gamma activator s may regulate cardiomyocyte hypertrophy at least partially through the NF- KB pathway.