Abstract
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 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-δ 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-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.
Highlights
The mortality rate of patients with acute myocardial infarction (MI) has dramatically improved due to the development of timely revascularization treatments
We found that the Peroxisome proliferator-activated receptors (PPARs)-δ agonist GW610742 treatment advances the onset of cardiac fibrosis and angiogenesis in the early infarct site after MI
This PPAR-δ agonist augmented the recruitment of bone marrow (BM)-derived mesenchymal stem cell (MSC) to injured heart tissues, the differentiation of fibroblasts into doi:10.1371/journal.pone.0148510.g007
Summary
The mortality rate of patients with acute myocardial infarction (MI) has dramatically improved due to the development of timely revascularization treatments. The healing process after MI involves repairing the infarcted myocardium, and is intertwined with left ventricular (LV) remodeling, which can result in heart failure [1]. During this healing process, the infarcted myocardium undergoes a series of cellular, molecular, histological, and extracellular responses, and can be divided into three overlapping phases: inflammation, proliferation, and maturation, which occur in a timed sequence [1,2]. The inflammation phase, the first step after MI, is characterized by degradation of the extracellular matrix, inhibition of tissue proliferation, and release of inflammatory mediators [3] During this period, the infarcted myocardium is vulnerable to the mechanical stress of cyclic intraventricular pressure and myocardial contractility. Acceleration of the healing process, fibrosis, is clinically critical for preventing cardiac rupture and progressive remodeling after MI
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