The Role of ERK1/2 Signaling Pathway in Coronary Microembolization-Induced Rat Myocardial Inflammation and Injury

Abstract

Aim: Inflammation plays an important role in coronary microembolization (CME)-induced myocardial injury. The present study was designed to investigate the role of extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathway in regulating myocardial inflammation and cardiac function in a rat model of CME. Methods: Sprague-Dawley rats were randomly divided into three groups: sham-operated group (sham group), CME group and PD98059 group (15 animals per group). CME was produced by injection of 42-µm microspheres into the left ventricle with occlusion of the ascending aorta. Rats in the PD98059 group were injected with PD98059, a specific ERK1/2 inhibitor, 30 min before the CME operation. Western blotting and immunohistochemistry analysis were used to determine the activation of ERK1/2. Echocardiography was employed to evaluate cardiac function. Hematoxylin-eosin staining was performed to assay myocardial inflammation. Expression of TNF-α mRNA was determined by RT-PCR analysis, and activity of NF-ĸB was assessed by electrophoretic mobility shift assay. Results: CME dramatically induced cardiac dysfunction (left ventricular ejection fraction, LVEF, was 72.97 ± 3.20% in the CME vs. 82.69 ± 3.50% in the sham group, p < 0.05) and local myocardial inflammatory response, both of which were ameliorated significantly by PD98059 (LVEF was 76.46 ± 4.46 and p < 0.05 vs. CME group). When compared to the CME group, PD98059 markedly attenuated the increased phosphorylation of ERK1/2 (0.48 ± 0.11 vs. 0.92 ± 0.10, p < 0.05), expression of TNF-α mRNA (0.42 ± 0.06 vs. 0.94 ± 0.04, p < 0.05) and activity of NF-ĸB (104.83 ± 13.65 vs. 540.79 ± 24.95, p < 0.05) in CME rat myocardium. Conclusions: The present study demonstrates a novel role of the ERK1/2 signaling pathway in promoting myocardium inflammation and dysfunction in CME, and suggests that ERK1/2 is a novel potential therapeutic target for CME.

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

“…Forty-five rats were randomized (random number) into three groups: sham, CME and CME plus TAK-242 ( n = 15 per group). The present study established a CME model by injecting plastic microspheres into the left ventricle (LV), as previously described [19, 20]. Briefly, a left lateral thoracotomy was undertaken in rats at the third and fifth intercostal space.…”

Effect of metoprolol on myocardial apoptosis after coronary microembolization in rats

“…The CME model was performed as described previously. [14,15] Briefly, the rats were anesthetized with 10% chloral hydrate (3 mL/kg, i.p.) and the trachea was intubated to maintain ventilation with a respirator.…”

The Involvement of Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) in the Regulation of Inflammation Following Coronary Microembolization

“…Many studies have shown that CME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-α (TNF-α) expression [6,7], resulting in damage to the myocardium and deterioration of myocardial systolic function [8,9]. Moreover, our previous studies also verified that microinfarction and ischemia in microembolized myocardium cause a severe inflammatory response with increased TNF-α expression in concert with the impairment of cardiac function [10,11]. …”

“…Our preliminary studies showed that a post-CME inflammatory response occurred as a result of the upregulation of TNF-α expression in the myocardium [10,11]. It has been well established that excessive TNF-α expression is derived from the surviving cardiomyocytes surrounding microinfarcts in autocrine or paracrine patterns [6] and is responsible for the detrimental effect on progressive contractile dysfunction [6,7,8,20,22].…”