51-OR: Vascular Sorbs2 Deficiency Is an Independent Risk of Vascular Complications in Diabetes

Introduction & Objective: We have recently reported that Sorbs2 (sorbin and SH3 domain-containing 2) proteins are abundantly expressed in vasculature and linked to BK channelopathies in Sorbs2 null mice. However, the role of Sorbs2 on vascular physiology is unknown.

Methods: We created the vascular smooth muscle cell (SMC)-specific Sorbs2 KO (SMC-Sorbs2 KO) mice. We examined BK channel activity and BK channel-mediated vasodilation in the coronary arteries of these animals as well as db/db and high-fat diet (HFD) diabetic mice.

Results: SMC-Sorbs2 KO mice at 6-7 months of age has normal body weights and blood glucose levels, but their coronary vasodilation to NS-1619 (a BK channel activator) was diminished by 41.52% * (n=7-12), which was associated with a 30% reduction of BK channel current density (defined as the iberiotoxin-sensitive K⁺ components) in freshly isolated coronary SMCs, compared to those of age-matched WT mice. Importantly, vascular Sorbs2 expression was downregulated by 58.82% * (n=6) and 51.12% * (n=4) in db/db mice and HFD mice, compared to nondiabetic controls. This was accompanied by decreased BK-α and BK-β1 protein levels by 76.0% and 69.74% in db/db mice and by 55.35% and 66.24% in HFD mice (n=6 for both), and by impaired BK channel activity and BK channel-mediated vasodilation in the coronary arteries of diabetic mice.

Conclusion: Sorbs2 is a key determinant of vascular BK channel physiology. Lack of vascular Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetes. Vascular Sorbs2 deficiency should be considered an independent risk of diabetic cardiovascular complications. *: p<0.05.