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Effects of Peroxisome Proliferator-Activated Receptor-? Agonist on Cardiac Healing after Myocardial Infarction.

ABSTRACT: Peroxisome proliferator-activated receptor-delta (PPAR-?)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-?-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-? agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-? expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-? agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.

SUBMITTER: Park JR

PROVIDER: S-EPMC4749247 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction.

Park Jeong Rang JR Ahn Jong Hwa JH Jung Myeong Hee MH Koh Jin-Sin JS Park Yongwhi Y Hwang Seok-Jae SJ Jeong Young-Hoon YH Kwak Choong Hwan CH Lee Young Soo YS Seo Han Geuk HG Kim Jin Hyun JH Hwang Jin-Yong JY

PloS one 20160210 2

Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrat ...[more]

PMID: 26862756

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Project description:Liver insufficiency and damage are major causes of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals, and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARbeta/delta-/- mouse is more susceptible to chemically induced hepatotoxicity than its wild-type counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARbeta/delta confers protection to hepatocytes. We hypothesized that PPARbeta/delta plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 4-HNE are PPARbeta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARbeta/delta subtype while 4-hyroxyhexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARbeta/delta activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARbeta/delta-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARbeta/delta activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

Dataset Information

Effects of Peroxisome Proliferator-Activated Receptor-? Agonist on Cardiac Healing after Myocardial Infarction.

Publications

Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction.

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