Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction

Abstract

Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1β, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin–angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

Preventive effect of hesperidin modulates inflammatory responses and antioxidant status following acute myocardial infarction through the expression of PPAR‑γ and Bcl‑2 in model mice

“…It is an important messenger in regulating energy metabolism, cell differentiation, proliferation, apoptotic and inflammatory reactions, endogenous synthesis and the secretion of active materials (32). It was previously suggested that PPAR-γ only existed in the differentiation of adipose cells, however, it has since been reported that PPAR-γ exists extensively on a variety of cells, including myocardial cells, myocardial fibroblasts, mononuclear/macrophages and vascular smooth muscle cells (9). In addition to its involvement in adipose cell differentiation, PPAR-γ also regulates gene transcription in the cardiovascular system, and the gene regulates lipogenesis and expression of the diabetes obesity gene (33).…”

“…PPAR-γ is also expressed in human vascular endothelial cells, vascular smooth muscle cells and mononuclear macrophages. PPAR-γ ligands can prevent the accumulation of inflammatory cells through inhibiting the expression of interleukin (IL)-8, monocyte chemoattractant protein 1 (MCP-1) and ICAM-1 (9,12). Studies have shown that the content of apoptotic factors in infarcted mice myocardial cells can be inhibited through drug pretreatment, including the expression of P53, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and Fas (13,14).…”

“…Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor. It belongs to the nuclear receptor super-family (9). PPARs are divided into three sub-types, namely PPARα, PPARβ and PPAR-γ (10).…”

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

“…For example, inflammatory mediators and PPARα ligand, leukotriene B4 can exert a negative feedback mechanism via PPARα activation to limit its activity and to resolve an inflammatory response [28]. PPARα also interferes with the proinflammatory activity of NF-κB by modulating the gene expression of IκB, an NF-κB inhibitor [29]. PPARα interacts with glucocorticoid receptor α or estrogen receptor to transrepress other proinflammatory transcription factors for anti-inflammatory effects [30,31].…”

ISN Forefronts Symposium 2015: Nuclear Receptors and Diabetic Nephropathy

“…Activated PPARα can prevent overexpression of proinflammatory molecules. 18 It was shown that the ligand activation of PPARα will increase the expression of fibroblast growth factor-21 (FGF-21), enhance the phosphatidylinositol-3 kinase/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK-3β)/Fyn-mediated nuclear factor (erythroid-derived 2)-like 2 signal, and prevent the development of DN. 19 PPARα activation improves lipotoxicity by activating adenosine monophosphate kinase-peroxisome proliferator-activated receptor g coactivator-1α (PGC-1α)-estrogen-related receptor-1α (ERR-1α)-forkhead box 03a (Fox03a) signaling and ameliorating glucose-induced matrix production and mesangial cell proliferation by inhibiting extracellular signal–regulated kinase 1/2 and phosphatidylinositol-3′-kinase/AKT activation, suggesting its potential for the treatment of DN.…”