Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis
EntityUAM. Departamento de Medicina
10.1186/s12933-018-0675-2Cardiovascular Diabetology 17.1 (2018): 31
Funded byThis work was supported by Grants SAF2011/22555, SAF2014-51795-R, SAF2016-80843-R from Ministerio de Ciencia e Innovación and (S2010/BMD- 2423) from Comunidad de Madrid to M. Benito and from CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
ProjectGobierno de España. SAF2011/22555; Gobierno de España. SAF2014-51795-R; Gobierno de España. SAF2016-80843-R; Comunidad de Madrid. S2010/BMD- 2423/MOR
SubjectsApoptosis; Atherosclerosis; Insulin receptor isoforms; Insulin-like growth factor receptor; Vascular smooth muscle cells; Medicina
Rights© 2018 The Author(s)
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
Background: Clinical 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. Methods: We 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. Results: We 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. Conclusions: In 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
Google Scholar:Beneit, Nuria - Martín-Ventura, José Luis - Rubio-Longás, Carlota - Escribano, Óscar - García-Gómez, Gema - Fernández, Silvia - Sesti, Giorgio - Hribal, Marta Letizia - Egido, Jesús - Gómez-Hernández, Almudena - Benito, Manuel
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