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

Abstract

Abstract. Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors, belong to the nuclear hormone receptor superfamily regulating expression of genes involved in different aspects of lipid metabolism, inflammation and cardiac energy production. Activation of PPAR-α isoform by its natural ligands, fatty acids (FA) and eicosanoids, promotes mitochondrial FA oxidation as the primary ATP-generating pathway. On the other hand, PPAR-γ regulates lipid anabolism or storage, while, until recently, the function of PPAR-β/δ has been less explored. Under conditions associated with acute or chronic oxygen deprivation, PPAR-α modulates expression of genes that determine substrate switch (FA vs. glucose) aimed at maintenance of basic cardiac function. Although PPAR-α and PPAR-γ synthetic agonists, hypolipidemic and antidiabetic drugs, have been reported to protect the heart against ischemia/ reperfusion injury, it is still a matter of debate whether PPAR activation plays a beneficial or detrimental role in myocardial response to ischemia, in particular, in pathological conditions. This article reviews some findings demonstrating the impact of PPAR activation on cardiac resistance to ischemia in normal and pathologically altered heart. Specifically, it addresses the issue of susceptibility to ischemia in the diabetic myocardium, with particular regards to the role of PPAR. Finally, involvement of PPAR in the mechanisms of lipid-independent cardioprotective effects of some hypolipidemic drugs is also discussed.

Mitochondrial performance in heat acclimation—a lesson from ischemia/reperfusion and calcium overload insults in the heart

“…I/R insult resulted in a drop of PGC-1␣ and NRF transcripts, together with increased transcript levels of genes coding lipid metabolic pathways in C and LTHA hearts, suggesting enhanced lipid utilization at that stage (21,31,55), irrespective of the acclimatory status. The only finding linked with acclimation status was the abolished upregulation of PPAR␥, PPAR␦ (associated with lipid metabolism), and Hadhb (associated iron metabolism) on the STHA mitochondria.…”

Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice

“…PPARs are nuclear receptor proteins coupled with retinoid X receptors (RXR) which act as transcription factors to regulate the expression of some genes mostly affecting lipid metabolism and energy balance in cells [13]. These transcription factors have three subtypes: PPAR-a, PPARb/d and PPAR-c, which have different expressions in various tissues [14].…”

M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes

“…The cell types used (see Methods section for details) were: THP-1 monocytic cells (THP1-Mon), M2-polarized THP-1 monocytes (THP1-M2Mon), PMA-differentiated THP-1 macrophages (dTHP1-MΦ), and M2-polarized PMA-differentiated THP-1 macrophages (dTHP1-M2MΦ). We have previously reported that intercalation of oxLDL-derived cholesterol into the ER membrane of oxLDL-treated THP1-Mon cells alters the physico-chemical properties of this membrane (as determined by Electron Paramagnetic Resonance spectrometry [23]), and so disrupts ER membrane protein function (as determined by coupled-enzyme SERCA2b Ca 2+ ATPase assays [23]).…”

“…Hence, UPRs lead either to restoration of normal cell physiology and cell survival, or to cell death [17]. Thus, excessive accumulation of cholesterol into macrophages can lead via UPR/CHOP-triggered apoptosis to lipotoxic macrophage cell death [20,21]; importantly, we and others have recently reported that oxLDL can trigger similar effects [22,23], due to liberation of free cholesterol from oxLDL particles that have been imported into macrophages, and trafficking of this free cholesterol to the ER membrane [16,20,23]. …”