Abstract 645: Atheroprotective Mechanism of Chromium Picolinate in Streptozotocin-Induced Diabetic ApoE-/- Mice

Abstract

Vascular disease accounts for increased morbidity and mortality in diabetes. Given the burden of health care expenditure in diabetics, relatively cost-effective strategies represent an attractive therapeutic approach. Trivalent chromium (Cr) is a mineral nutrient reported to have a beneficial role in glycemic and cardiovascular health. While previous studies suggest that Cr reduces vascular inflammation in diabetes, the precise mechanisms of Cr action in the large blood vessels in diabetes remain unknown. We showed earlier that Cr picolinate (CrP, a bioavailable form of Cr) in vitro downregulates a potent proatherogenic matricellular protein thrombospondin-1 (TSP-1) in glucose-stimulated vascular smooth muscle cells. The present study provides the first evidence of an atheroprotective mechanism of Cr in vivo in a mouse model of diabetic atherosclerosis. Briefly, hyperglycemia was induced in male ApoE -/- mice (6wks age) with 50mg/Kg/day streptozotocin (STZ), i.p. for 5 consecutive days. Hyperglycemic mice (blood glucose>250mg/dl) on regular chow diet were treated with or without CrP (8μg/Kg) in drinking water starting at 8 wks of age and all mice were sacrificed at 18 wks of age. Using en face atherosclerotic lesion assay shown by Oil red O staining, we demonstrated that CrP in vivo significantly prevents development of lesion in aortic vessel walls of hyperglycemic STZ-ApoE -/- mice compared to untreated STZ-ApoE -/- mice. Consistently, high-frequency ultrasound imaging of common carotid artery revealed that CrP prevents development of vascular lesions in STZ-ApoE -/- mice while untreated mice showed more pronounced lesions with a significant reduction (20%) in carotid artery diameter. Importantly, atheroprotective effects of CrP were accompanied by a significant decrease (>35%) in TSP-1 and PCNA (proliferation marker) expression in aortic vessels of STZ-ApoE -/- mice, shown by immunoblotting. Also, en face studies showed that knockout of TSP-1 protects STZ-induced hyperglycemic ApoE -/- mice against atherosclerosis. Together, our results suggest that CrP in vivo prevents diabetic atherosclerosis via downregulation of TSP-1 in the large blood vessel wall, underscoring TSP-1 as a novel therapeutic target in diabetic atherosclerosis.