Beneficial effects of PPAR-? ligands in ischemia?reperfusion injury, inflammation and shock

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR-gamma regulates gene expression by forming a heterodimer with the retinoid X receptor (RXR) before binding to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby regulating several metabolic pathways, including lipid biosynthesis and glucose metabolism. Thiazolidinediones (TZDs, i.e. rosiglitazone, pioglitazone), which are synthetic PPAR-gamma agonists, act as insulin sensitizers and are used in the treatment of type 2 diabetes. In the last few years, it has, however, become evident that the therapeutic effects of PPAR-gamma ligands reach far beyond their use as insulin sensitizers. Recently, PPAR-gamma has been implicated as a regulator of cellular inflammatory and ischemic responses. PPAR-gamma agonists may exert their anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation, by either PPAR-gamma-dependent or -independent mechanisms. Several lines of evidence suggest that TZDs protect the heart and other organs against the tissue injury caused by ischemia/reperfusion (I/R) injury and shock. This review discusses the anti-inflammatory signalling pathways activated by PPAR-gamma, as well as the potential therapeutic effects of PPAR-gamma agonists in animal models of ischemia/reperfusion, inflammation and shock.

Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2

“…It has recently become evident that the therapeutic effects of TZDs reach far beyond use as insulin sensitizers. Recently, several lines of evidence have suggested that TZDs protect the heart and other organs against tissue damage caused by I/R injury (2). I/R has been shown to activate the pro-survival kinase signaling cascades, p42/p44 extracellular signal-regulated kinases (ERK1/2), which have been implicated in cell survival through recruitment of antiapoptotic pathways of protection (3).…”

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

“…14,15 In addition to targeting VSMCs, wherein they suppress proliferation and migration, MMPs production and Ang II receptor type 1 (AT1) expression, [16][17][18] PPARg agonists have recently been shown to possess anti-inflammatory and antiarteriosclerotic properties by antagonizing Ang II effects. [19][20][21] The TLR4 signaling activates mitogen-activated protein kinases and production of interferon-gamma-inducible protein 10 (IP-10), in turn activating protein kinase C (PKC) and finally resulting in the translocation of NF-kB. [22][23][24] Recent studies have revealed that the TLR4 signaling plays a central role in atherosclerosis, [25][26][27] thus providing an important link between inflammation, innate immunity and atherosclerosis.…”

The role of PPAR in myocardial response to ischemia in normal and diseased heart

“…In addition to PPAR transactivation, stimulation of PPAR can also negatively regulate gene expression in a liganddependent manner by inhibiting the activities of other transcription factors, such as activated protein-1 (AP-1), nuclear factor-kappaB (NF-κB), nuclear factor of activated T-cells (NFAT) or signal transducer and activator of transcription (STAT) via mechanism known as ligand-dependent transrepression (Abdelrahman et al 2005). In contrast to transcriptional activation, transrepression does not involve binding of PPAR to response elements of the target genes but direct interaction with other transcription factors and co-repressors or modulation of kinase activity.…”

“…Research suggests that PPAR may exert beneficial effects by negatively regulating the expression of pro-inflammatory genes in inflammation-related diseases including myocardial ischemia/reperfusion injury (Abdelrahman et al 2005). Several mechanisms have been suggested to account for this activity including ligand-independent repression of the transcription of target genes via binding of PPAR to response element in the absence of ligands and recruitment of the co-repressor complexes (reviewed by Collino et al 2008).…”

“…The latter indicates that the maintenance of enhanced PPAR gene expression during I/R may contribute to improved outcome of myocardial I/R injury in the diabetic heart, at least in the early phase of the disease. Moreover, this protective effect of PPAR up-regulation might possibly involve not only metabolic effects of PPARs but also their anti-inflammatory and antioxidative effects (Delerive et al 2001;Smeets et al 2007), through the negative regulation of NF-κB (Abdelrahman et al 2005), that might be of particular importance in the diabetic myocardium. In line, Khandoudi et al (2002) have shown that cardioprotective effects of PPAR-γ activation in diabetic rat hearts exposed to global I/R is associated with inhibition of Jun NH(2)-terminal kinase phosphorylation.…”