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.

Public Health Relevance

Cardiovascular and associated pulmonary diseases (CVPD) are the number one cause of death in industrialized countries, and smoking is a major risk factor for CVPD. The present study examines how nicotine, the addictive component of cigarette smoke, alters the homeostasis of the renin-angiotensin system and predisposes nicotine users to CVPD. Findings from this study will help us better inform the public of the danger associated with nicotine use, and may also lead to improved treatment for nicotine- associated CVPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL135635-04S1
Application #
10222924
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Cooper, Lawton S
Project Start
2017-01-01
Project End
2021-11-30
Budget Start
2020-07-27
Budget End
2020-11-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Physiology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Oakes, Joshua M; Fuchs, Robert M; Gardner, Jason D et al. (2018) Nicotine and the Renin-Angiotensin System. Am J Physiol Regul Integr Comp Physiol :
Yue, Xinping; Basting, Tyler M; Flanagan, Thomas W et al. (2018) Nicotine Downregulates the Compensatory Angiotensin-Converting Enzyme 2/Angiotensin Type 2 Receptor of the Renin-Angiotensin System. Ann Am Thorac Soc 15:S126-S127
Basting, Tyler; Lazartigues, Eric (2017) DOCA-Salt Hypertension: an Update. Curr Hypertens Rep 19:32