Peroxisome proliferator-activated receptor (PPAR) gene profiling uncovers insulin-like growth factor-1 as a PPARalpha target gene in cardioprotection.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARα, PPARβ/δ, and PPARγ. 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 PPARα 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 PPARα and the involvement of a PPARα/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.
Hubrecht Institute and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, 3584 CS Utrecht, The Netherlands.
Hamid
H
el Azzouzi
Stefanos
S
Leptidis
Meriem
M
Bourajjaj
Anne-Sophie
AS
Armand
Roel
R
van der Nagel
Marc
M
van Bilsen
Paula A
PA
Da Costa Martins
Leon J
LJ
De Windt
D000818:Animals; D017209:Apoptosis; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000737:chemistry*; D020033:Protein Isoforms; D051381:Rats; D015427:Reperfusion Injury
D008055:Lipids; D047493:PPAR alpha; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I
Cell. 1999 Apr 16;97(2):189-98
10219240
Nat Cell Biol. 2010 Dec;12(12):1220-7
21102440
J Biol Chem. 2001 Nov 30;276(48):44390-5
11574533
Cardiovasc Res. 2005 Jul 1;67(1):21-9
15896727
J Mol Cell Cardiol. 2008 Jun;44(6):968-75
18462747
Endocrinology. 1996 Jan;137(1):354-66
8536636
Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1899-904
16339830
J Biol Chem. 1993 Dec 25;268(36):26817-20
8262913
Circ Res. 1998 Sep 7;83(5):516-22
9734474
Nucleic Acids Res. 2004 Sep 08;32(16):4742-9
15356291
J Clin Invest. 2002 Jan;109(1):121-30
11781357
Mol Cell Biol. 2000 Jul;20(14):5119-28
10866668
Nat Med. 2000 May;6(5):556-63
10802712
Nat Med. 2004 Nov;10(11):1245-50
15475963
Cardiovasc Res. 2009 Feb 15;81(3):420-8
18854380
J Cardiovasc Pharmacol. 2005 Apr;45(4):301-9
15772517
J Biol Chem. 2002 Dec 13;277(50):48617-26
12226086
Circ Res. 2005 Jun 24;96(12):e92-e101
15933268
Circulation. 2003 Oct 28;108(17):2034-40
14581381
Physiology (Bethesda). 2007 Feb;22:56-64
17289931
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):303-8
11756685
J Biol Chem. 2005 Jun 3;280(22):21594-9
15793309
Acta Physiol (Oxf). 2007 Nov;191(3):171-88
17935522
J Biol Chem. 2001 Apr 6;276(14):10853-60
11278377
Cell. 1999 Oct 29;99(3):335-45
10555149
Genes Dev. 1996 Apr 15;10(8):974-84
8608944
J Toxicol Sci. 2006 Dec;31(5):471-90
17202761
J Lipid Res. 2006 Jul;47(7):1583-7
16585784
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8031-5
7644533
J Pharmacol Exp Ther. 2007 Apr;321(1):165-71
17215446
Cardiovasc Res. 2007 Aug 1;75(3):519-29
17543901
Physiol Genomics. 2004 Jun 17;18(1):33-42
15054141
Cardiovasc Res. 2007 Nov 1;76(2):269-79
17678635
Circulation. 1995 Jan 15;91(2):393-402
7805243
J Clin Invest. 2002 Jul;110(2):271-9
12122119
Circ Res. 1999 May 14;84(9):1007-19
10325238
Anal Biochem. 2005 Sep 1;344(1):8-15
16038868
J Biol Chem. 2008 Aug 8;283(32):22295-303
18477567
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1226-31
12552126
J Clin Invest. 2007 Dec;117(12):3930-9
18037994
J Neurochem. 1999 Aug;73(2):521-31
10428047
Circ Res. 2003 Mar 21;92(5):518-24
12600885
Circulation. 2006 Jul 25;114(4):298-308
16847152
Circulation. 2003 Nov 11;108(19):2393-9
14557369
Circulation. 1999 Jun 22;99(24):3125-31
10377075
Diabetes. 2001 Dec;50(12):2809-14
11723064
J Biol Chem. 2003 May 2;278(18):15927-34
12590133