TY - JOUR
T1 - Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPAR alpha Target Gene in Cardioprotection
AU - el Azzouzi, Hamid
AU - Leptidis, Stefanos
AU - Bourajjaj, Meriem
AU - Armand, Anne-Sophie
AU - van der Nagel, Roel
AU - van Bilsen, Marc
AU - Martins, Paula A. da Costa
AU - De Windt, Leon J.
PY - 2011/4/22
Y1 - 2011/4/22
N2 - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPAR alpha, PPAR beta/delta, and PPAR gamma. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPAR alpha activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPAR alpha and the involvement of a PPAR alpha/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.
AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPAR alpha, PPAR beta/delta, and PPAR gamma. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform-specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643-mediated PPAR alpha activation in the wild-type mouse heart resulted in up-regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPAR alpha and the involvement of a PPAR alpha/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.
U2 - 10.1074/jbc.M111.220525
DO - 10.1074/jbc.M111.220525
M3 - Article
C2 - 21245137
SN - 0021-9258
VL - 286
SP - 14598
EP - 14607
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -