Abstract
Hyperglycemia and obesity, characteristic of metabolic syndrome (MetS), are important risk-factors for atherosclerosis. MetS patients manifest increased vascular smooth muscle cell (VSMC) migration and proliferation, hallmark of VSMC phenotypic transition, critical for evolution of atherosclerosis. We previously reported that high glucose and high leptin independently upregulate a potent proatherogenic matricellular protein, Thrombospondin-1 (TSP-1), expression in VSMC. The goal of the present study was to interrogate the role of TSP-1 in SMC de-differentiation and development of atherosclerosis in MetS. We utilized a mouse model of combined MetS and atherosclerosis (KKAy +/- /ApoE -/- ) generated by crossing obese hyperglycemic agouti KKAy +/- mice with atherosclerotic ApoE -/- . Upon weaning (4 wks age), male yellow KKAy +/- /ApoE -/- and age-matched black KKAy -/- /ApoE -/- littermates on standard lab diet were monitored monthly for body weight and blood glucose. At 24 wks age, mice were harvested after overnight fasting; plasma, aorta and heart were collected for biochemical, molecular and lesion studies. Prior to harvest, mice were subjected to treadmill exercise test at an incline with progressively increasing speed until exhaustion. At 16 wks age, yellow KKAy +/- /ApoE -/- mice showed significant increase in body weight and random blood glucose levels (<0.0001) vs. black KKAy -/- /ApoE -/- littermates, validating the MetS phenotype. Peak oxygen consumption (VO 2max ), maximum running speed and total run time until exhaustion were significantly reduced in MetS KKAy +/- /ApoE -/- mice (p<0.003 vs. non-MetS KKAy -/- /ApoE -/- ), suggesting impaired cardiovascular fitness. Aortic root morphometry revealed 4-fold increase in lesion lipid burden in MetS vs non-MetS mice. This was accompanied with reduced LMOD (SM contractile marker) and SRF (transcriptional activator of SM contractile genes) expression in aortic vessels of MetS mice (p<0.04 vs. non-MetS mice). Notably, lesion abundance and reduced SMC differentiation associated with increased TSP-1 expression in the aortic vasculature of MetS mice. Together, our data suggest a putative role of TSP-1 in SMC de-differentiation and atherosclerotic lesion formation in metabolic syndrome.
Published Version
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