Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis

Abstract

BackgroundClinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear.MethodsWe evaluated IR isoforms expression in human carotid atherosclerotic plaques by consecutive immunoprecipitations of insulin receptor isoform B (IRB) and IRA. Western blot analysis was performed to measure IGF-IR, IGF-IIR, and α-smooth muscle actin (α-SMA) expression in human plaques. The expression of those proteins, as well as the presence of apoptotic cells, was analyzed by immunohistochemistry in experimental atherosclerosis using BATIRKO; ApoE−/− mice, a model showing more aggravated vascular damage than ApoE−/− mice. Finally, apoptosis of VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs), was assessed by Western blot against cleaved caspase 3.ResultsWe observed a significant decrease of IRA/IRB ratio in human complicated plaques as compared to non-complicated regions. Moreover, complicated plaques showed a reduced IGF-IR expression, an increased IGF-IIR expression, and lower levels of α-SMA indicating a loss of VSMCs. In experimental atherosclerosis, we found a significant decrease of IRA with an increased IRB expression in aorta from 24-week-old BATIRKO; ApoE−/− mice. Furthermore, atherosclerotic plaques from BATIRKO; ApoE−/− mice had less VSMCs content and higher number of apoptotic cells. In vitro experiments showed that IGF-IR inhibition by picropodophyllin induced apoptosis in VSMCs. Apoptosis induced by thapsigargin was lower in IR−/− VSMCs expressing higher IGF-IR levels as compared to IRLoxP+/+ VSMCs. Finally, IRB VSMCs are more prone to thapsigargin-induced apoptosis than IRA or IRLoxP+/+ VSMCs.ConclusionsIn advanced human atherosclerosis, a reduction of IRA/IRB ratio, decreased IGF-IR expression, or increased IGF-IIR may contribute to VSMCs apoptosis, promoting plaque instability and increasing the risk of plaque rupture and its clinical consequences.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0675-2) contains supplementary material, which is available to authorized users.

Microarray analysis of the time‑dependent expression profiles of long non‑coding RNAs in the progression of vein graft stenotic disease

“…According to a previous study, overexpression of Insr-A, one of the isoforms of Insr, confers a proliferative advantage on VSMCs in the early stages of the atherosclerotic process (43). Furthermore, decreased Insr-A/Insr-B ratio may also contribute to apoptosis of VSMCs and increased risk of atherosclerotic plaque rupture (22). Mcam, an endothelial transmembrane protein of the immunoglobulin superfamily, has been reported to be involved in several important signaling pathways in vascular disease, including PI3K/AKT, p38 and PKC (23).…”

“…A total of 8,041 lncRNAs ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ enrichment analysis, nine biological processes associated with the vascular remodeling process were selected. Moreover, co-expression network analysis revealed an association between lncRNAs and their target genes, which were reported to play roles in mediating vascular disorders (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Furthermore, it was found that AF062402, one of the significantly upregulated lncRNAs, may serve a role in inducing vein graft restenosis.…”

“…Based on the results of functional analysis, a total of 360 lncRNAs and 135 associated protein-coding genes were predicted to be involved in the vascular remodeling process (Table SI). Among these, 194 lncRNAs and seven previously reported associated protein-coding genes (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) involved in mediating vascular disease were selected to construct a co-expression network. Each protein-coding gene was targeted by multiple lncRNAs (Fig.…”

Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque

“…IGF-IIR is a foetal promoter of cell growth, survival and differentiation 50 . During atherosclerosis IGF-IIR overexpression may have a protective role in macrophages and a detrimental role in VSMCs or unstable atherosclerotic plaques 51,52 . Moreover, IGF-IIR activates caspase 3 in cardiomyocytes, promoting apoptosis 53 .…”

The role of smooth muscle cells in calcification of atherosclerotic plaques

“…The serum concentration of IGF-I is regulated by growth hormone (GH), therefore it is considered the local mediator of GH's systemic effects 242 . Both IGF-I and IGF-II promote cartilage matrix formation in form of collagen I and non-collagenous matrix proteins and have been implicated during atherosclerotic plaque formation 253 as well as intimal hyperplasia 254 . Thyroid hormone and tri-iodothyronine (T3) are systemic factors stimulating hypertrophy and death of chondrocytes as well as hypertrophic markers including collagen X and AP 255 .…”