Peroxisome Proliferator-activated Receptor (PPAR) Gene Profiling Uncovers Insulin-like Growth Factor-1 as a PPARα Target Gene in Cardioprotection

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPAR␣, PPAR␤/␦, and PPAR␥. 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␣ 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␣ and the involvement of a PPAR␣/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions.

The Relationship between Serum Insulin-Like Growth Factor I Levels and Ischemic Stroke Risk

“…Fourth, IGF-I plays a main role in restoring mitochondrial dysfunction during aging by increasing mitochondrial membrane potential, reducing oxygen consumption, and increasing ATP synthesis, which in turn minimize the cytochrome release to the cytoplasm and subsequently promote neural survival by decreasing caspase-induced apoptosis [35]. Azzouzi et al [36] confirmed the role of the IGF-I signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions. Impaired IGF-I signaling has already been linked to increased oxidative stress and mitochondrial dysfunction in neuronal cells [37].…”

Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1

“…Activation of PPARa by fenofibrate has an anti-cancer effect and attenuates signaling responses of IGF1R in medulloblastoma and glyoma cell lines (Urbanska et al 2008, Drukala et al 2010. In contrast, PPARa activation in the heart, through Wy-14643 administration, results in upregulation of Igf1 expression in myocytes and subsequent protection against ischemia/reperfusion-induced apoptosis (El Azzouzi et al 2011). A possible explanation is that either fenofibrate or Wy-14643 acts on the IGF1 system in a PPARa-independent manner.…”

Insulin‐like growth factors and their potential role in cardiac epigenetics

“…This signalling loop can be potentially responsible for epigenetic activity that targets survival, proliferation and/or differentiation of cardiac cells. Physical effort has been shown to increase levels of IGF-I in muscle and physiological cardiac hypertrophy, thus inducing the IGF-I/ PI3K/Akt/P70S6K signalling pathway, and thereby increasing the protein synthesis required to build muscle; all of this can be epigenetically regulated [34,60,153,154]. On the other hand, PPAR-c ligands (such as rosiglitazone) activate tuberous sclerosis complex-2 (TSC2) inhibiting mTOR signalling [152,155] intrauterine growth restriction (IUGR), where a decrease in postnatal IGF-I mRNA variants is associated with histone 3 tri-methylation of lysine 36 at the igf1 gene (H3Me3K36).…”