Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis

Abstract

IR increases plaque vulnerability by augmenting the CX3CL1/CX3CR1 axis, which is mechanistically linked to reduced VSMC survival. Thus, modulation of IRS2-dependent signalling emerges as a potential therapeutic strategy to promote VSMC survival and atheroma plaque stability and to reduce inflammatory mediators in IR-MetS.

Decidual macrophages: key regulators of vascular remodeling in human pregnancy

“…In turn, the decidual macrophages up-regulate expression of the eat me signal receptor LRP-1. VSMCs' expression of fractalkine and calreticulin has been reported previously [35,36], but their expression has not been characterized in terms of VSMC apoptosis and the potential ability to attract phagocytes. Fractalkine is a chemokine expressed by cells undergoing apoptosis to attract phagocytes, whereas calreticulin is constitutively expressed as a cytosolic protein that moves to the outer membrane in apoptotic cells, serving as an anchor for the phosphatidyl serine flip, characteristic of apoptosis [34].…”

Insulin resistance as a predictor of cardiovascular morbidity and end-stage renal disease

“…IR is considered an important risk factor for both atherosclerotic cardiovascular disease and type 2 DM and a key determinant of cardiovascular risk factors (Kobayashi, Oka, & Maesato, 2008;Martínez-Hervás & Vinué, 2014;Sciacqua et al, 2013;Semenkovich, 2006), although, some studies failed to prove the relationship between IR and atherosclerotic events (Howard, O'Leary, Zaccaro, et al, 1996a;Semenkovich, 2006;Wingard, Barrett-Connor, & Ferrara, 1995). Several mechanisms through which impaired insulin resistance could result in atherosclerosis are pointed out in the literature: the insulin anti-aggregating platelet effect, the inhibition by insulin of migration of vascular smooth muscle cells, the effect of the hormone on nitric oxide release from the endothelium, the inhibitory effect of the hormone on fibrinogen synthesis and also the promotion of a proinflammatory and prooxidant state (Bonora et al, 2002;Cannizzo, Luján, Estrella, et al, 2012;Martínez-Hervás & Vinué, 2014).…”

“…Several mechanisms through which impaired insulin resistance could result in atherosclerosis are pointed out in the literature: the insulin anti-aggregating platelet effect, the inhibition by insulin of migration of vascular smooth muscle cells, the effect of the hormone on nitric oxide release from the endothelium, the inhibitory effect of the hormone on fibrinogen synthesis and also the promotion of a proinflammatory and prooxidant state (Bonora et al, 2002;Cannizzo, Luján, Estrella, et al, 2012;Martínez-Hervás & Vinué, 2014).…”

Ink4/Arf locus restores glucose tolerance and insulin sensitivity by reducing hepatic steatosis and inflammation in mice with impaired IRS2-dependent signalling

“…RNA (0.5-1 μg) from mouse liver and macrophages, obtained using TRIzol Reagent (Invitrogen Carlsbad, CA, USA), was retrotranscribed with the Maxima First-Strand cDNA Synthesis kit and amplified with Luminars Colour-HiGreen/High ROX qPCR MasterMIX (Fermentas, Madrid, Spain) on a thermal Cycler 7900 Fast System as previously described [35]. Results were analysed with the provided software (Applied Biosystems, Madrid, Spain).…”

“…The proliferation rate was determined as the percentage of BrdUpositive cells relative to the total cell count analysed in 10 randomly selected fields (with a total of 600-1000 cells) of 4-6 independent coverslips per replicate. Macrophage apoptosis was analysed in cells irradiated or not irradiated with ultraviolet (UV) light (60 J/m 2 ) and rested for 18 h. Cell apoptosis was determined by flow cytometry as the SubG0 peak subpopulation (in percentage) in cells fixed with 80% ethanol (−20°C for 30 min) and stained with propidium iodide (50 μg/mL, containing RNase A, Sigma) as described [35]. Two experiments were performed, each with quadruplicates, and between 5000-15,000 events were analysed in each replicate.…”