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

Aims Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPAR beta agonists were suggested as potential drugs for the treatment of metabolic syndrome, but effects of PPAR beta activation on cardiac growth and vascularization are unknown. Thus, we investigated the consequences of pharmacological PPAR beta activation on the heart and the underlying molecular mechanisms. Methods and results Male C57/Bl6 mice were injected with the specific PPAR beta 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 PPAR beta stimulation were compared with hearts of mice undergoing long-term voluntary exercise or pharmacological PPAR alpha 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 PPAR beta significantly stimulated the activity of the CnA promoter, (iii) PPAR beta protein bound directly to the CnA promoter, (iv) the CnA target genes NFATc3, Hif-1 alpha, and Cdk 9 were upregulated in response to PPAR beta stimulation, and (v) the inhibition of CnA activity by cyclosporine A abolished the hypertrophic and angiogenic responses to PPAR beta stimulation. Conclusion Our data suggest PPAR beta pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass.