Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-γ, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury

Abstract

This study was conducted to evaluate whether treatment of normal and diabetic rat hearts with rosiglitazone, a high-affinity ligand of the peroxisome proliferator-activated receptor-␥ (PPAR-␥) used for the treatment of type 2 diabetes, improves postischemic functional recovery. The effects of acute rosiglitazone administration were investigated using working hearts isolated from normal rat or rats diabetic for 4 weeks after streptozotocin (STZ) injection. Hearts were subjected to 30 min of normothermic, zero-flow ischemia followed by 30-min reperfusion. Rosiglitazone (1 mol/l) administered before ischemia had no effect on cardiac function during baseline perfusion, but it significantly improved aortic flow during reperfusion in both normal and diabetic hearts. In a chronic protocol in which rosiglitazone was given by daily gavage (10 mol/kg body wt) immediately after STZ injection, rosiglitazone also prevented postischemic injury and significantly improved functional recovery. Using Western immunoblotting, it was demonstrated that the acute cardioprotective effect of rosiglitazone is associated with an inhibition of Jun NH 2 -terminal kinase phosphorylation in both normal and diabetic rat hearts. Furthermore, rosiglitazone also inhibited activating protein-1 DNAbinding activity. These data, demonstrating that rosiglitazone limits postischemic injury in isolated hearts, suggest an important function for PPAR-␥ in the heart. Diabetes

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

“…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. Recently, Collino et al (2011) have demonstrated that acute activation of PPAR-β/δ by its selective agonist GW0742 conferred protection against renal I/R injury in rats with STZ-induced diabetes.…”

“…The two available TZDs, rosiglitazone and pioglitazone, are currently used alone or in combination with other oral anti-diabetic agents (Theocharis et al 2004). These drugs are known as insulin sensitizers stimulating the tissue uptake of glucose in the diabetics (Sidell et al 2002), however, their action extends far beyond their hypoglycemic activity (Khandoudi et al 2002;Shiomi et al 2002;Lee et al 2003). Table 2 summarizes currently known PPAR modulators, as well as clinically important PPAR-α and PPAR-γ agonists, fibrates and glitazones, respectively.…”

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

“…5 The expression of PPARG is essential for fat cell differentiation and normal lipid metabolism in adipose tissue. 40 Various long-chain fatty acids 20 and chemical compounds 23 can bind to and activate PPARG, leading to changes in mRNA expression of target genes. 26 Besides PPARG, LXRA and SREBF1 are 2 key transcription factors also involved in lipid metabolism.…”

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

“…9 DUSP8 is reported to act specifically via JNK and p38 MAPK, unlike extracellular signal-regulated kinase. 8 Recent reports show that TZDs modulate JNK expression and activity in cardiac ischemia reperfusion injury 10 and in insulinresistant brains, which results in reduction of tau phosphorylation. 11 Hence, we examined JNK and DUSP8 as possible mechanisms for the neuroprotective effect observed after treatment with rosiglitazone after cerebral ischemia.…”