BCCMA: Integrating Nutrition and Metabolic Monitors to Mitigate Cardiometabolic Disparities in our Veterans (VA-iMITIGATE): Metabolic Regulation of Vascular Function in Diabetes

Portland Va Medical Center, Portland OR

Investigators

Abstract

Abstract Vascular calcification, which leads to arterial stiffness and exacerbates cardiovascular complications, is a prevalent issue among patients with diabetes mellitus. Currently, there is no effective therapy for vascular calcification. The Veterans Affairs Diabetes Trial has revealed elevated vascular calcification in the Veterans, but lipid-lowering statins failed to inhibit the disease progression. Therefore, a comprehensive understanding of the pathogenesis of vascular calcification and stiffness in diabetic is urgently needed to address the unmet scientific and clinic needs. Vascular smooth muscle cells (VSMC) and endothelia cells (EC), the two main cell types in the vascular wall, contribute to diabetic vascular calcification and stiffness. VSMC dedifferentiation and osteogenic differentiation are emerging as the key determinant for vascular calcification. In addition, endothelial mesenchymal transition (EndoMT) and osteogenesis has been lined to vascular calcification in diabetic mice. However, the interplays of EC and VSMC in diabetic vasculopathy and the regulation by metabolic cues are largely unknown. Elevated O-GlcNAcylation is found in human diabetic carotid plaques and diabetic mouse arteries. Our preliminary studies determined increased vascular O-GlcNAcylation in clinically relevant high-fat diet (HFD)-induced type II diabetes mouse model, and uncovered a direct regulation of glucose on O-GlcNAcylation in EC, which was associated with increased markers EndoMT. Emerging evidence has demonstrated an important role of EndoMT in cardiovascular diseases, however its regulation and functional roles in regulating diabetic vasculopathy is largely unknown. Knockdown of O-GlcNAc transferase (OGT), the O-GlcNAcylation enzyme, in EC inhibited diabetic conditions-induced EndoMT markers, supporting a novel function of O-GlcNAcylation in regulating EndoMT. Furthermore, we identified a causative link of O-GlcNAcylation in mediating high glucose-induced oxidative stress and NADPH oxidases, the producers of hydrogen peroxide (H2O2). We have recently shown that EC-derived H2O2 induces VSMC expression of Runx2, the master osteogenic factor that promotes VSMC calcification, in mouse arteries. Therefore, O-GlcNAcylation-induced H2O2 by EC may promote calcification of VSMC in diabetes. In addition, O-GlcNAcylation deficiency in VSMC attenuated diabetic conditions-induced Runx2 and VSMC calcification, suggesting the intrinsic elevation of O-GlcNAcylation in VSMC is critical for diabetic VSMC calcification. Taken together, these new findings support the hypothesis that inhibition of EC-derived O- GlcNAcylation may mitigate diabetes-induced EC dysfunction and inhibit the initiation and progression of diabetic vasculopathy. Two aims are proposed to 1) Characterize the effects of endothelial cell-specific OGT deletion on diabetic vasculopathy, using our newly generated EC-specific OGT deletion mice; and 2) Elucidate the mechanisms underlying O-GlcNAcylation-dependent diabetic vasculopathy. With the expertise and resource synergy in our multidisciplinary teams, the collaborative program will provide new insights to fill the knowledge gaps, which may lead to novel strategies for clinical management or treatment of diabetic vasculopathy.