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.