# Chronic nicotine inhalation increases susceptibility to cardiovascular and pulmonary diseases through inhibition of local compensatory mechanisms

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2021 · $396,097

## Abstract

Project Summary
 Nicotine is the addictive component of tobacco-derived products. Through binding to a family of
nicotinic acetylcholine receptors (nAChRs), nicotine influences a diverse range of cellular mechanisms
involved in homeostasis and disease. Although cigarette smoking is a major risk factor for cardiovascular
and pulmonary diseases (CVPD) including hypertension, vascular dysfunction and fibrosis, the direct
effects and the molecular mechanisms of nicotine in the pathogenesis of these diseases have not been
elucidated. Our preliminary data show that cigarette smoke or direct nicotine inhalation disrupts the
homeostasis of the renin-angiotensin system (RAS). The role of the RAS in the regulation of blood
pressure and the development of CVPD through neurovascular and cardiopulmonary mechanisms has
been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased
sympathetic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release
and inflammation, contributing to tissue fibrosis, endothelium dysfunction and hypertension. Angiotensin
Converting Enzyme type 2 (ACE2) cleaves Ang-II into the vasodilator peptide Ang-(1-7), hence a pivotal
player in the ACE2/Ang-(1-7)/Mas receptor compensatory axis of the RAS. AT2R, another receptor
for Ang-II, opposes the deleterious effects of AT1R activation, and ACE2-formed Ang-(1-7) was
recently shown to activate not only the Mas receptor but also AT2R. Our pilot data suggest that cigarette
smoke or nicotine inhalation inhibits the expression of ACE2/AT2R in multiple organs including the brain,
heart and lungs, thus disrupting the balance within the RAS. Accordingly, the central hypothesis of this
application is: Chronic nicotine inhalation disrupts RAS homeostasis through inhibition of local
compensatory mechanisms, leading to increased susceptibility to cardiovascular and pulmonary
diseases. Taking advantage of the combined expertise of our multidisciplinary team, we will use state-
of-the-art molecular, cellular and pharmacological tools combined with novel transgenic and knockout
murine models (ACE2 overexpression and knockout) to assess the direct effects of inhaled nicotine on
cardiovascular, autonomic and pulmonary functions. We will address the following Specific Aims:
1) Chronic nicotine inhalation impairs local compensatory activity within the RAS; 2) Chronic nicotine
inhalation increases susceptibility to CVPD; 3) Chronic nicotine inhalation adversely affects the
treatment for CVPD. Findings from this study will advance our understanding of the pathogenic
mechanisms linked to inhaled nicotine, and set the basis for future development of improved treatment
to preserve RAS compensatory activity in CVPD.

## Key facts

- **NIH application ID:** 10075952
- **Project number:** 5R01HL135635-05
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Jason Davin Gardner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,097
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075952

## Citation

> US National Institutes of Health, RePORTER application 10075952, Chronic nicotine inhalation increases susceptibility to cardiovascular and pulmonary diseases through inhibition of local compensatory mechanisms (5R01HL135635-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10075952. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*