More than 29 million Americans, including children and adults, are living with diabetes and its prevalence is still on the rise in the United States. Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients, accounting for almost 2 out of 3 deaths. In particular, diabetes aggravates the development of atherosclerosis, which is the usual cause of heart attack, stroke, and peripheral vascular diseases. Thus, minimization of the risk of CVD is a critical clinical goal in the management of diabetic patients. To date, no particular diabetes medication or combination of medications is considered superior to afford cardiovascular benefits. An increasing body of studies, including ours, uncovered evidence that KLF11 is a key factor in regulating glucose signaling in pancreatic ?-cells and hepatic lipid metabolism. KLF11 gene polymorphisms are associated with human T2D. Indeed, KLF11 gene mutation causes MODY7, an early-onset T2D. However, the functions and detailed mechanisms of KLF11 in diabetes-associated cardiovascular complications remain largely unexploited. Our preliminary work identifies KLF11 as an anti-inflammatory factor in endothelial cells (EC) and here we present evidences that KLF11 is a glucose responsive gene, displays potent antioxidant and anti-inflammatory effects in EC in vitro and KLF11 deficiency aggravates diabetic atherosclerosis in vivo. Hence, we hypothesize that KLF11 protects the vasculature from atherogenesis by inhibiting endothelial cell oxidative stress through TXNIP, to be addressed by systematically implementing gain- and loss-of-KLF11 function strategies both in vitro and in vivo under diabetic and euglycemic conditions. First, we will define the role and molecular mechanisms of KLF11 in ECs oxidative stress in vitro (Aim 1). Next, leveraging our unique EC-specific KLF11 transgenic and knockout mouse models, available and specifically generated for this study, we will determine the role of KLF11 in the development of diet-induced atherosclerosis (Aim 2). Based on preliminary results and the field at large, we expect that KLF11 exerts protective effects in diabetes-associated atherosclerosis mainly through modulating redox genes, especially down-regulating thioredoxin interacting protein (TXNIP) in the presence of proatherogenic stimuli. This study will provide greater mechanistic insight into the overall KLF11 biology in the endothelium and, together with the new resources generated, will aid in future design of novel drugs to treat diabetes and associated CVD.

Public Health Relevance

Krppel-like factor 11 (KLF11) gene mutations causes an early-onset type 2 diabetes mellitus, MODY7 (maturity-onset diabetes of the young, type VII). We propose to define the protective roles and underlying molecular mechanisms of KLF11 on vascular endothelial cells in atherosclerosis, which is the primary cause of mortality among diabetic patients. The proposed work will have profound implications regarding the maintenance of vascular homeostasis and treatment of CVD associated with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL138139-01
Application #
9368283
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Chen, Jue
Project Start
2017-07-01
Project End
2022-04-30
Budget Start
2017-07-01
Budget End
2018-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109