# Sorbs2 targeting and BK channel regulation in the coronary artery of patients with type 1 diabetes

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $688,424

## Abstract

Project Summary
Type 1 diabetes (T1D) is strongly associated with coronary heart disease. However, the molecular mechanism
underlying coronary vascular pathology, especially coronary arterial smooth muscle pathology in human with
T1D is incomplete. Vascular BK channels, composed of four pore-forming subunits (BK-α) and four regulatory
subunits (BK-β1), are densely expressed in coronary artery smooth muscle cells (SMCs) and are a key
determinant of coronary blood flow and cardiac function. Over the last 10 years, we and other investigators
have demonstrated that coronary BK channel function is impaired in T1D animals due to increased oxidative
stress and it contributes to a worse outcome in myocardial ischemia. However, most of our knowledge of
coronary BK channel dysregulation in T1D is obtained from animals and most of studies are focused on the
BK-β1 dysregulation in diabetes. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a component of
cytoskeleton proteins in vascular SMCs. Sorbs2 is abundantly expressed in cardiovascular tissues and is a
downstream target of Nrf2. However, the role of Sorbs2 in vascular pathophysiology is unknown. We have
exciting preliminary results showing that Sorbs2 interacts with BK-α and BK-β1 protein and regulates BK
channel expression in coronary SMCs. Interestingly, Sorbs2 knockout mice share many common features of
coronary BK channelopathy with diabetes, despite being normoglycemic and not obese, indicating that Sorbs2
deficiency is an independent risk of vascular BK channelopathy. Importantly, Sorbs2 expression is significantly
reduced in coronary arteries of patients with T1D. Unlike T2D patients, the expression of BK-α, but that of BK-
β1, is markedly reduced in the coronary SMCs of patients with T1D. However, the role of Sorbs2 on coronary
BK channelopathy and vasculopathy of human T1D has not been established, and the underlying mechanisms
regarding the downregulation of BK-α expression in coronary SMCs of T1D patients is unclear. In this project,
we will take advantage of the availability of human coronary arteries from T1D patients who are scheduled for
cardiac surgery at Mayo Clinic in Rochester (MN) to test our hypothesis that downregulation of Sorbs2
expression contributes to BK channel and vascular dysfunction in the coronary arteries of T1D patients and
increase of Sorbs2 expression by pharmacological Nrf2 activation protects coronary BK channel function and
vasoreactivity in human tissues with T1D. Results from this study will provide novel insights into the molecular
mechanisms underlying BK channelopathy and coronary vasculopathy in T1D and may help develop new
strategies for the treatment of cardiovascular complications in T1D patients.

## Key facts

- **NIH application ID:** 10507884
- **Project number:** 1R01HL161821-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Tong Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,424
- **Award type:** 1
- **Project period:** 2022-08-05 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10507884

## Citation

> US National Institutes of Health, RePORTER application 10507884, Sorbs2 targeting and BK channel regulation in the coronary artery of patients with type 1 diabetes (1R01HL161821-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10507884. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*