# Kruppel-like factor 11 (KLF11) and atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $453,529

## Abstract

PROJECT SUMMARY/ABSTRACT
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 β-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.

## Key facts

- **NIH application ID:** 10144494
- **Project number:** 5R01HL138139-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jifeng Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $453,529
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144494

## Citation

> US National Institutes of Health, RePORTER application 10144494, Kruppel-like factor 11 (KLF11) and atherosclerosis (5R01HL138139-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10144494. Licensed CC0.

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