Peroxisome proliferator-activated receptor beta stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin.

AIMS Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPARbeta agonists were suggested as potential drugs for the treatment of metabolic syndrome, but effects of PPARbeta activation on cardiac growth and vascularization are unknown. Thus, we investigated the consequences of pharmacological PPARbeta activation on the heart and the underlying molecular mechanisms. METHODS AND RESULTS Male C57/Bl6 mice were injected with the specific PPARbeta agonists GW0742 or GW501516, or vehicle. Cardiomyocyte size and vascularisation were determined at different time points. Expression differences were investigated by quantitative reverse transcriptase-polymerase chain reaction and western blotting. In addition, the effects of PPARbeta stimulation were compared with hearts of mice undergoing long-term voluntary exercise or pharmacological PPARalpha activation. Five hours after GW0742 injection, we detected an enhanced angiogenesis compared with vehicle-injected controls. After 24 h, the heart-to-body weight ratios were higher in mice injected with either GW0742 or GW501516 vs. controls. The increased heart size was due to cardiomyocyte enlargement. No signs of pathological cardiac hypertrophy (i.e. apoptosis, fibrosis, or deteriorated cardiac function) could be detected. The effects are mediated via calcineurin A (CnA) activation as: (i) CnA was upregulated, (ii) GW0742 administration or co-transfection of PPARbeta significantly stimulated the activity of the CnA promoter, (iii) PPARbeta protein bound directly to the CnA promoter, (iv) the CnA target genes NFATc3, Hif-1alpha, and Cdk 9 were upregulated in response to PPARbeta stimulation, and (v) the inhibition of CnA activity by cyclosporine A abolished the hypertrophic and angiogenic responses to PPARbeta stimulation. CONCLUSION Our data suggest PPARbeta pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass.

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