# Mechanisms of Nicotine Inhalation-Induced Cardiovascular Disease

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $430,278

## Abstract

Abstract
Epidemiological, clinical and animal model research has shown that tobacco cigarette smoke (TCS) is a major
risk factor for cardiovascular disease (CVD) and metabolic disorders such as hypertension, coronary heart
disease, dyslipidemia, and diabetes. Nicotine (NIC), the addicting chemical of TCS, is believed to play a major
role in much of the damage induced by TCS. Chronic NIC inhalation has been observed to play a pathogenic
role in the induction and progression of CVD. NIC can induce direct coronary spasm and ischemia. It also
stimulates both autonomic ganglia and nerve terminals and upregulates numerous vasoconstrictors,
inflammatory mediators, cytokines and oxidative markers that play a role in inducing cardiovascular disease.
Vascular endothelial dysfunction (VED) and inflammation with enhanced reactive oxygen species (ROS)
formation have been detected in many cardiovascular and metabolic disorders associated with NIC exposure.
However, fundamental questions remain regarding: 1) the underlying mechanisms by which NIC inhalation
(NICI) induces CVD; 2) the correlation between disease and the dose of NIC delivered during exposure; 3) the
temporal effects of the dose of NIC delivered on the progression of disease; and 4) possible pharmacological
approaches to minimize, arrest or reverse NICI-induced disease. Our research plan will provide answers to
these questions using a controlled mouse model with available genetic modifications to explore the disease
mechanisms. There are 3 specific aims: 1) To determine the duration and dose intensity required to induce
NICI-mediated CVD and VED in a controlled mouse NICI model. The effects of NIC on heart rate, blood
pressure, heart structure and function, vascular reactivity, endothelial nitric oxide (NO) production that is critical
for normal vascular function, endothelial NO synthase (eNOS), leukocyte activation and ROS formation will be
determined. 2) With the doses and duration of NICI that produce CVD and VED, the molecular mechanisms
involved will be elucidated. The basis for the alterations in NO production will be determined by investigating
the effects of NICI on eNOS levels and functional state, as modulated by its critical cofactor tetrahydrobiopterin
(BH4), eNOS redox modification by S-glutathionylation, and its oxidative degradation. The role of leukocyte or
tissue NADPH oxidase will be determined with superoxide production from this enzyme measured along with
the expression and cellular localization of its subunits. Mice will be studied with knockout of critical NADPH
oxidase subunits to assess the role of this critical enzyme in CVD and VED. Superoxide dismutase (SOD)
over-expressing transgenic mice will be used to assess the role of superoxide. 3) With the knowledge obtained
on the mechanism of NIC-induced CVD, we will evaluate interventions aimed at preventing or ameliorating
NICI-induced CVD and VED. This research will provide important insights toward understanding the
process...

## Key facts

- **NIH application ID:** 10071191
- **Project number:** 5R01HL135648-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** JAY Louis ZWEIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $430,278
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071191

## Citation

> US National Institutes of Health, RePORTER application 10071191, Mechanisms of Nicotine Inhalation-Induced Cardiovascular Disease (5R01HL135648-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071191. Licensed CC0.

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