Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 7, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp106
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PPARβ stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin
1 INSERM U907, 06107 Nice, France
2 Université de Nice-Sophia Antipolis, 06108 Nice, France
3 Service de Microscopie Electronique Université de Nice-Sophia Antipolis, 06108 Nice, France
4 INSERM, UMR S621, Paris, 75013 France
5 Université Pierre et Marie Curie-Paris 6, UMR S621, Paris, 75013 France
Address for correspondence: Paul Grimaldi, INSERM U907, 28, Avenue Valombrose, 06107 Nice, France, Phone : +33 493 81 84 96, Fax: +33 493 81 54 32, e-mail: paul.grimaldi{at}unice.fr Kay-Dietrich Wagner, INSERM U907, 28, Avenue Valombrose, 06107 Nice, France Phone : +33 493 81 84 98Fax: +33 493 81 54 32 E-mail: kwagner{at}unice.fr
Aims: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPARβ agonists were suggested as potential drugs for the treatment of metabolic syndrome, but effects of PPARβ activation on cardiac growth and vascularisation are unknown. Thus, we investigated the consequences of pharmacological PPARβ activation on the heart and the underlying molecular mechanisms.
Methods: Male C57/Bl6 mice were injected with the specific PPARβ agonists GW0742 or GW501516, or vehicle for different time points and cardiomyocyte size and vascularisation determined. Expression differences were investigated by quantitative RT-PCR and Western Blotting. In addition, the effects of PPARβ stimulation were compared to hearts of mice undergoing long-term voluntary exercise or pharmacological PPAR
activation.
Results: Already after 5 hours of GW0742 injection, we detected an enhanced angiogenesis compared to vehicle-injected controls. After 24 hours, 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 PPARβ significantly stimulated the activity of the CnA promoter, III) PPARβ protein bound directly to the CnA promoter, IV) the calcineurin A target genes NFATc3, Hif-1, and Cdk 9 were upregulated in response to PPARβ stimulation, and V) inhibition of CnA activity by cyclosporine A abolished the hypertrophic and angiogenic responses to PPARβ stimulation.
Conclusion: Our data suggest PPARβ pharmacological activation as a novel approach to increase cardiac vascularisation and cardiac muscle mass.
KEYWORDS Angiogenesis; Calcineurin; Gene transcription; Hypertrophy; Peroxisome proliferator-activated receptor
Time for primary review: 25 Days