Activation of MAP Kinase In Vivo Follows Balloon Overstretch Injury of Porcine Coronary and Carotid Arteries

Abstract

Vascular restenosis involves contraction, proliferation, and remodeling of the arterial wall in response to overstretch injury. Mitogen-activated protein kinases (MAPKs) are implicated in both contraction and proliferation of vascular smooth muscle (VSM), and studies of porcine carotid arterial muscle strips have shown that mechanical stretch leads to the activation of the extracellular signal-regulated kinase (ERK) family of MAPKs in vivo. We, therefore, analyzed the acute effect of mechanical overstretch injury on ERK-MAPK (herein referred to simply as MAPK) activity in porcine coronary and carotid arteries in vivo. Balloon angioplasty catheters were inflated to 6 atm three times over 5 minutes at a balloon-artery ratio of 1.2:1 in either porcine coronary or carotid arteries. The arteries were snap-frozen after angioplasty, and MAPK activity was measured. Angioplasty of the left anterior descending (LAD, n = 5), left circumflex (LCx, n = 5), and carotid (n = 5) arteries effected an increase in MAPK activity compared with the activity in uninstrumented right coronary arteries (RCAs) or carotid arteries from the same animals used for controls. Balloon angioplasty of carotid arteries led to an increase in MAPK activity that was 7.7-fold over the activity in control arteries and comparable to the activity in stretched carotid arterial muscle strips in vivo. The increase in coronary artery kinase activity on angioplasty was variable from animal to animal. The increase in MAPK activity over that in control arteries ranged from 4.5- to 31.7-fold (mean +/- SEM, 10.7 +/- 5.3) in the LAD and 1.8- to 31.3-fold (mean +/- SEM, 9.7 +/- 5.7) in the LCx. There were no apparent inherent differences in the levels of MAPK activity in the three different types of coronary arteries (RCA, LAD, and LCx) without instrumentation. MAPK activation occurs rapidly during angioplasty, suggesting that this kinase may play an early role in initiating the injury response in both porcine coronary and carotid arteries. MAPKs may be key enzymes targeted to treat or prevent restenosis.

Tissue Factor Binding of Activated Factor VII Triggers Smooth Muscle Cell Proliferation via Extracellular Signal–Regulated Kinase Activation

“…All these events may occur in the vessel wall after plaque rupture. Although previous reports have demonstrated the activation of MAP kinases in arteries in animal models of balloon injury and neointimal formation, [25][26][27][28] our study provides evidence that TF can link activation of blood coagulation and SMC proliferation. In this respect, inhibition of these new functions of TF may represent a novel, attractive therapeutic target.…”

Profilin, and Vascular Diseases

“…Consistent with our finding, very recent studies showed increased profilin-I expression in hypertrophic thoracic aorta and mesenteric arteries of spontaneously hypertensive rats with subsequent elevation in both P-ERK and P-JNK, suggesting that profilin-I may contribute to the vascular remodeling in these rats (Cheng et al, 2011;Zhong et al, 2011). In this context, previous studies suggested that mechanical stretch is closely related to JNK and ERK1/2 activation (Hu et al, 1997;Pyles et al, 1997). These cascades play an important role in remodeling of blood vessels, as well.…”

Cudratricusxanthone A Isolated from the Root Bark of Cudrania tricuspidata Inhibits the Proliferation of Vascular Smooth Muscle Cells through the Suppression of PDGF-Receptor Beta Tyrosine Kinase

“…The MAPK signaling pathway is considered to be a critical step in the proliferation of VSMCs 12) and Pyles et al reported that MAPKs were activated in response to balloon overstretch injury in porcine carotid arteries. 7) Using balloon injured carotid artery, it was demonstrated that MAPK signaling, especially ERK1/2, is increased and that medial cell replication following injury is reduced by PD098059. 13) ERK1/2 (a MAPK family member) plays a central role on cell growth regulation, and recently this pathway was found to be involved by triggering Ras-Raf activation, MEK phosphorylation, and ERK1/2 phosphorylations in the proliferative effect of PDGF-BB in VSMCs.…”

“…6,7) Therefore, an understanding of its inhibition on PDGF-BBstimulated VSMC proliferation is important in terms of developing methods of treating cardiovascular disease.…”

“…5) PDGF-BB activates the extracellular regulated kinases 1 and 2 (ERK1/2) by triggering the activation of RasRaf-MEK, and its activation is known to be associated with the development and progression of proliferative cardiovascular diseases, such as hypertension and atherosclerosis. 6,7) Therefore, an understanding of its inhibition on PDGF-BBstimulated VSMC proliferation is important in terms of developing methods of treating cardiovascular disease.…”