Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 8, Pages 4104-4117Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122237
Keywords
-
Categories
Funding
- British Heart Foundation [PG/15/44/31574, FS/18/38/33659]
- Diabetes UK [12/0004458]
- Medical Research Council [MR/K003291/1]
- Diabetes Research & Wellness Foundation [DRWF PP/2017]
- Jean Shanks Foundation
- Innovative Medicines Initiative (the SUMMIT consortium) [IMI-2008/115006]
- Wellcome Trust [072960/Z/03/Z]
- MRC [MR/K003291/1] Funding Source: UKRI
Ask authors/readers for more resources
Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased beta-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and beta-amyloid (A beta) are linked with vascular disease development and increased BACE1 and A beta accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Ap, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A beta 42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A beta 42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A beta 42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A beta 42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A beta 42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A beta 42. Lowering A beta 42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available