# Role of Trimethylamine-N-oxide in endothelial dysfunction

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2024 · $384,375

## Abstract

Project Summary
Cardiovascular diseases (CVDs) are implicated in 50% of deaths in developed countries and is thus a major
health concern and we still remain far from a cure. In addition to the traditional risk factors for CVDs, the
influence exerted by gut microbial metabolites on the pathogenesis of CVDs has been recognized only in
recent times. Trimethylamine-N-oxide (TMAO), a gut microbe-derived metabolite of dietary
phosphatidylcholine/carnitine is elevated in the circulation of CVD patients and has been associated with
atherosclerosis and CVD progression in rodents and humans. The present grant proposal attempts to define
novel molecular signaling mechanisms mediating the responses of arterial endothelial cells (ECs) to TMAO,
which will provide new insights into the pathogenesis of endothelial dysfunction and vascular injury associated
with atherosclerosis. Our preliminary results have shown that TMAO induced Nlrp3 inflammasomes have direct
actions on the endothelial cells. Thus TMAO induces both inflammatory and non-inflammatory effects leading
to endothelial dysfunction and ultimately atherosclerosis. These represents novel pathogenic mechanisms of
TMAO beyond inflammation. Based on these observations, we hypothesize that gut microbial metabolites such
as TMAO which are released into the circulation act as endogenous danger signals and induce both
inflammatory and non-inflammatory responses leading to endothelial dysfunction and vascular injury which
consequently manifests into atherogenesis in the arterial wall. To test this hypothesis, we will address how
TMAO induces endothelial dysfunction and atherosclerosis in in vivo using Nlrp3-/- mice, endothelium-specific
Nlrp3 knockout mice (EC-Nlrp3-/-) and their wild type littermates. We will then investigate the non-inflammatory
effects of TMAO leading to endothelium dependent vasodilation, pyroptosis and DAMPs production both in
vitro and in vivo. Lastly, we will explore the novel molecular signaling pathways mediating TMAO-induced
endothelial exosome release leading to endothelial dysfunction and vascular injury. The proposed studies will
reveal new mechanistic insights of CVD pathogenesis induced by microbial metabolites such as TMAO and will
pave way to the development of clinically relevant, novel therapeutic strategies for treating atherosclerosis and
resulting CVDs.

## Key facts

- **NIH application ID:** 10896250
- **Project number:** 5R01HL148711-03
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Sai Sudha Koka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,375
- **Award type:** 5
- **Project period:** 2022-08-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896250

## Citation

> US National Institutes of Health, RePORTER application 10896250, Role of Trimethylamine-N-oxide in endothelial dysfunction (5R01HL148711-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10896250. Licensed CC0.

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