Activation of Mitogen-Activated Protein Kinases in the Non-Ischemic Myocardium of an Acute Myocardial Infarction in Rats.

Abstract

fter myocardial infarction (MI), contractile impairment in the ischemic myocardium (IM) occurs suddenly and the non-ischemic myocardium adapts to the increased workload. Thereafter, the myocardial properties and morphology begin to change as the ventricular remodeling during the clinical course. The ventricular remodeling is accompanied by progressive chamber dilatation and subsequently an increased incidence of sudden death and congestive heart failure. [1][2][3][4][5] In the IM, the structural rearrangement is characterized by myocardial cell damage, inflammatory change and expression of extracellular matrix components. Furthermore, ventricular dilatation and myocardial hypertrophy can occur in the non-ischemic regions. 6 The process of ventricular remodeling after an acute myocardial infarction (AMI) involves topographical alternations in the ischemic and non-ischemic regions, 1,2 so an understanding of the myocardial response to AMI is important for appropriate therapeutic management.We previously reported that mitogen-activated protein kinases (MAPKs) are rapidly activated in the IM, followed by activation of transcriptional factors of activator protein 1 (AP-1) and mRNA expression of transforming growth factor -1, collagen types I and III, -myosin heavy chain, -skeletal actin and atrial natriuretic peptide. 7,8 MAPKs are a ubiquitous group of protein serine/threonine kinases and are important mediators of the signal transduction pathways responsible for cell growth, proliferation and apoptosis. [9][10][11][12] Therefore, this signal transduction system may be a key regulatory mechanism allowing cells to respond and eventually adapt to changes in myocardial ischemia. Although enhanced expression of the mRNAs was also observed in the non-ischemic region of the acutely infarcted heart, 7,8,13 the corresponding activities of MAPKs in that region are still unknown. The present study investigated whether the signal-transduction pathway of the non-ischemic myocardium shifted to ventricular remodeling after AMI by examining the myocardial activities of extracellular signal-regulated kinases (ERKs), c-Jun NH2 terminal kinases (JNKs) and p38MAPK, plus the AP-1 DNA binding activities in both the ischemic and non-ischemic regions of an infarcted rat heart. Furthermore, to clarify the possible cause of MAPKs activation, we measured the geometrical changes of the infarcted heart using echocardiography and then estimated the stretch and workload of the infarcted heart. Methods Production of the AMIMale Wistar rats weighing 290-310g (Clea Japan, Osaka, Japan) were used in the experiments. Myocardial infarction was produced as described previously. 7,8,14 Briefly, the rats were anesthetized by intraperitoneal injection of pentobarbital sodium (35 mg/kg). After intratracheal intubation, a left thoracotomy was performed under volume-controlled Activation of Mitogen-Activated Protein Kinases in the Non-Ischemic Myocardium of an Acute Myocardial Infarction in RatsKen Yoshida, MD; Minoru Yoshiyama, MD; Takashi Omura, MD; Yasuh...

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

“…βARRs are known to be involved, either directly or indirectly, in the regulation of a number of transcription factors that could regulate CCR2 gene transcription, including AP-1 and NF-κB (33)(34)(35)(36)(37). Although the role of AP-1 has been minimally studied following MI (38,39), it plays a well-established role in inflammation (40). We have demonstrated that βARR2-dependent β2AR signaling via AP-1 is required for CCR2 up-regulation in response to sympathetic stimulation, and that restoration of GRK/βARR-dependent β2AR signaling in immune cells rescues CCR2 expression, migration in response to CCL2, and cardiac infiltration following MI in vivo.…”

Hyperglycemia suppresses cardiac stem cell homing to peri-infarcted myocardium via regulation of ERK1/2 and p38 MAPK activities

“…The role of MAPKs in pathological cardiac remodeling has been investigated in several studies. After experimental MI, ERK1/2, JNK1/2 and p38 MAPK were found to be activated in both ischemic myocardium and unaffected portions of the left ventricle in mice and rats (31,32). In the process of cardiac remodeling after MI, the activation of the p38 MAPK and JNK1/2 cascades promoted fibrosis in the infarct area and unaffected myocardium, but the role of the ERK1/2 cascade is not well known (33,34).…”

Activation of mitogen activated protein kinases in post-infarcted patients

“…Several studies have investigated the role of MAPKs in pathological cardiac remodeling. MAPKs such as JNK1/2 and p38a MAPK are activated in the minutes after experimental myocardial infarction, in both the ischemic myocardium and unaffected portions of the left ventricle of mice and rats [21,22]. The MAPK family consists of p38 MAPK, extracellular signal regulated protein kinase (ERK), and c-Jun NH2-terminal protein kinase (JNK).…”