Implication of Insulin Receptor A Isoform and IRA/IGF-IR Hybrid Receptors in the Aortic Vascular Smooth Muscle Cell Proliferation: Role of TNF-α and IGF-II

Abstract

To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR(-/-) VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-α induced in a ligand-dependent manner a higher association between IRA and TNF-α receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-α induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-α treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-α or IGF-II, which might be of significance in the early atherosclerotic process.

Inhibition of microRNA-25 by tumor necrosis factor α is critical in the modulation of vascular smooth muscle cell proliferation

“…The presence of chronic or mild inflammation in the arteries is a risk factor for cardiovascular disease (26,27) and TNF-α is a potent inflammatory cytokine. TNF-α has been reported to possess the ability to induce vascular damage and promote the pathogenesis of atherosclerosis (8,28). In addition, TNF-α is known to regulate the proliferation and migration of VSMCs, which results in calcium deposition and an increase in arterial stiffness (12,29,30).…”

Ox-LDL Upregulates IL-6 Expression by Enhancing NF-κB in an IGF2-Dependent Manner in THP-1 Macrophages

“…During atherogenesis, circulating monocytes migrate into the arterial intima where the majority of them differentiate into macrophages [34]. After uncontrolled uptake of ox-LDL via different scavenger receptors, macrophages are transformed into lipid-laden foam cells and produce inflammatory cytokines, growth factors, and cytotoxic oxygen and nitrogen radical molecules that drive the growth and inflammatory responses of atherosclerotic plaque [35]. Hence, atherosclerosis is an inflammatory process in which the macrophage is the cardinal player.…”

“…Nevertheless, little attention has focused on IGF2 in the progression of atherosclerosis. Recently, evidences confirmed IGF2 as an important factor involved in the development of cardiovascular disease, especially in vascular muscle cells [35,37]. Yet, little is known about the role of IGF2, particularly in ox-LDLstimulated THP-1 macrophages.…”

Insulin Promotes Proliferation and Migration of Breast Cancer Cells through the Extracellular Regulated Kinase Pathway

“…The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen (Belardi et al, 2013). Insulin, through ERK signaling, induced a proliferation in vascular smooth muscle cells (VSMCs) (Gomez et al, 2013). The present study demonstrates new findings that insulin promotes the growth of breast cancer in the nude mice and increases the proliferation and migration of MCF-7 human breast cancer cells via ERK pathway.…”

“…Insulin, through ERK signaling, induced a proliferation in vascular smooth muscle cells (Gomez et al, 2013). However, whether insulin is through ERK signaling in the breast cancer to regulate the proliferation and migration is not well clear.…”