Increasing evidence suggests thrombospondin-1 (TSP-1), a potent proatherogenic matricellular protein, as a putative link between hyperglycemia and atherosclerotic complications in diabetes. We previously reported that the micronutrient chromium picolinate (CrP), with long-standing cardiovascular benefits, inhibits TSP-1 expression in glucose-stimulated human aortic smooth muscle cells in vitro. Here, we investigated the atheroprotective action of orally administered CrP in type 1 diabetic apolipoprotein E-deficient (ApoE−/−) mice and elucidated the role of TSP-1 in this process. CrP decreased lipid burden and neointimal thickness in aortic root lesions of hyperglycemic ApoE−/− mice; also, smooth muscle cell (SMC), macrophage and leukocyte abundance was prevented coupled with reduced cell proliferation. Attenuated lesion progression was accompanied with inhibition of hyperglycemia-induced TSP-1 expression and reduced protein O-glycosylation following CrP treatment; also, PCNA and vimentin (SMC synthetic marker) expression were reduced while SM-MHC (SMC contractile marker) levels were increased. To confirm a direct role of TSP-1 in diabetic atherosclerosis, hyperglycemic TSP-1−/−/ApoE−/− double knockout mice were compared with age-matched hyperglycemic ApoE−/− littermates. Lack of TSP-1 prevented lesion formation in hyperglycemic ApoE−/− mice, mimicking the atheroprotective phenotype of CrP-treated mice. These results suggest that therapeutic TSP-1 inhibition may have important atheroprotective potential in diabetic vascular disease.

Vascular disease is the leading cause of increased morbidity and mortality in diabetes. Risks of atherosclerotic complications are enhanced two-to-four-fold in diabetic patients1,2, accounting for >80% of deaths and hospitalizations in these individuals. Clinical studies, including recent animal data3,4,5,6,7, indicate that elevated glucose levels, independent of hyperlipidemia, may have profound proatherogenic effects in diabetes. Previous epidemiological studies1,2 have revealed a strong association between cumulative glycemic exposure and intima-media thickness (IMT) of the carotid artery, an early marker of atherosclerosis. Together, these reports support the notion that hyperglycemia is an important risk factor for development of macrovascular complications in diabetes. However, mechanisms underlying hyperglycemia-induced atherosclerosis are incompletely understood.

Thrombospondin-1 (TSP-1), a potent proatherogenic and anti-angiogenic protein, belongs to a family of matricellular proteins controlling cell-cell and cell-matrix interactions8. Earlier studies have shown that TSP-1 expression is significantly enhanced in response to vascular injury and in atherosclerotic lesions, with augmented expression in vascular smooth muscle cells (VSMC)9,10,11. Growing literature indicates distinct cell-and tissue-specific effects of TSP-1; both in vivo and in vitro studies have revealed that TSP-1 stimulates VSMC proliferation12 while inducing endothelial cell (EC) apoptosis13. The TSP protein family has been previously linked to atherosclerotic vascular disease based on GENEQUEST studies demonstrating an association between specific single nucleotide polymorphisms in the TSP genes with coronary artery disease and myocardial infarction14. These findings, confirmed by multiple human studies, lend support to TSP-1 as an alternative pathway for development of atherosclerosis.

Diabetic patients and diabetic animal models have been reported to have elevated TSP-1 levels in the plasma and walls of the large blood vessels15,16. Earlier work demonstrated that high glucose in vitro, characteristic of a diabetic milieu, upregulates TSP-1 expression in cells of the large blood vessel (VSMC, EC, fibroblasts)16. We have further shown that hyperglycemia in vitro increases TSP-1 expression via a transcriptional mechanism in primary human aortic smooth muscle cell (HASMC) cultures17,18.