# Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $517,273

## Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to mutations in the
LDLR gene, characterized by severely elevated levels of LDL-C and increased risk of premature atherosclerotic
cardiovascular disease (ASCVD). Although lowering LDL-C is the undisputed primary goal of therapy, there is
mounting evidence that HDL function is impaired in FH. A major hypothesis of this project is that dysfunctional
HDL contributes to the residual inflammatory risk of cardiovascular events in FH patients. Reactive dicarbonyls
including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids
impairing HDL function. We have discovered that ApoAI and HDL are modified by MDA and IsoLG in FH and
that HDL function is dramatically impaired in terms of cholesterol efflux capacity, as well as anti-inflammatory
and antioxidant functions. Furthermore, we have recently discovered that two small molecule dicarbonyl
scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce
atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of significant changes in plasma lipid
levels. In addition, the lesions were characterized by a dramatic reduction in necrosis, which was associated with
increased macrophage survival and efferocytosis. The lesions had features of stable atherosclerotic plaques,
suggesting the hypothesis that dicarbonyl scavengers promote lesion remodeling, inflammatory resolution and
plaque stabilization. Therefore, in Specific Aim 1, we will examine the hypothesis that dicarbonyl scavengers are
capable of remodeling pre-existing atherosclerotic lesions in Ldlr-/- mice. We will examine the hypothesis that
improved HDL function promotes inflammatory resolution as characterized by increased macrophage
efferocytosis and increased Tregs, contributing to the antiatherogenic mechanisms of dicarbonyl scavengers. In
addition, we will test the hypothesis that the atheroprotective effects of dicarbonyl scavenging are in large part
due to preservation of HDL functions by performing atherosclerosis studies in HDL deficient Ldlr-/-ApoAI-/- vs.
Ldlr-/- mice. In Aim1c, we will examine the hypothesis that macrophage scavenger receptors, CD36 and SR-BI,
play critical roles in mediating the impact of reactive dicarbonyls on atherosclerosis. These mechanistic studies
of the impact of dicarbonyl scavengers on atherosclerosis will set the stage for a clinical translational study in
humans. Recent Phase I studies with 2-HOBA have demonstrated its safety in humans. Therefore, in Specific
Aim 2, we will test the hypothesis that 2-HOBA will reduce modification of HDL and improve HDL function in
humans with heterozygous FH and in subjects with coronary artery disease without FH. The impact of 2-HOBA
on HDL small RNAs will be examined. Finally, we will test the hypothesis that α-Me-2-HOBA will have improved
pharmacokinetic attributes and better ability to reduce at...

## Key facts

- **NIH application ID:** 10089340
- **Project number:** 2P01HL116263-06A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** MACRAE F LINTON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,273
- **Award type:** 2
- **Project period:** 2014-06-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089340

## Citation

> US National Institutes of Health, RePORTER application 10089340, Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH (2P01HL116263-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10089340. Licensed CC0.

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