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Principal Investigator: Jason Davin Gardner
Organization: LSU HEALTH SCIENCES CENTER
Fiscal Year: 2020
Award: $312,700
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Address><Affect><Aldosterone><Ang I (1-7)><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin II Receptor><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Antidiuretic Hormone><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Autoregulation><BP control><BP homeostasis><BP management><BP regulation><Binding><Body Tissues><Brain><Brain Nervous System><CD143 Antigens><Carboxycathepsin><Cardiac Failure Congestive><Cardiopulmonary><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cause of Death><Cell Communication and Signaling><Cell Signaling><Chronic><Cigar><Cigarette><Cleaved cell><Congestive Heart Failure><Data><Developed Countries><Development><Dipeptidyl Peptidase A><Disease><Disorder><Dysfunction><Electronic cigarette><Encephalon><Equilibrium><Family><Fibrosis><Functional disorder><Future><Heart><Heart Decompensation><Heart Vascular><Homeostasis><Hydrogen Oxide><Hypertension><Hypotensive Agent><Hypotensive Drugs><Hypotensives><Impairment><Industrialized Countries><Industrialized Nations><Inflammation><Infusion><Infusion procedures><Intracellular Communication and Signaling><Kininase A><Kininase II><Knock-out><Knockout><Lead><Link><Lung><Lung Respiratory System><Lung diseases><Mediating><Mice><Mice Mammals><Molecular><Molecular Interaction><Murine><Mus><Myocardial depression><Myocardial dysfunction><Nicotine><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Organ><Pathogenesis><Pathogenicity><Pathologic><Pb element><Peptides><Peptidyl-Dipeptidase A><Pharmacology><Physiological Homeostasis><Physiopathology><Play><Predisposition><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Hypertension><Receptor Protein><Renin-Angiotensin System><Reporting><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Role><Signal Transduction><Signal Transduction Systems><Signaling><Smoker><Smoking><Sodium Chloride><Susceptibility><System><Tissues><Tobacco><Transgenic Organisms><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasopressins><Water><angiotensin I (1-7)><angiotensin-(1-7)><arm><balance><balance function><beta-Hypophamine><biological signal transduction><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><blood vessel disorder><cardiac dysfunction><cardiac fibrosis><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><cell type><chronic heart failure><cigarette smoke><cigarette smoking><cigarette use><circulatory system><cleaved><coronary fibrosis><developed country><developed nation><developed nations><developmental><disease of the lung><disorder of the lung><e-cig><e-cigarette><ecig><ecigarette><endothelial dysfunction><heart dysfunction><heavy metal Pb><heavy metal lead><high blood pressure><hookah><hyperpiesia><hyperpiesis><hypertensive disease><improved><loss of function><lung disorder><lung fibrosis><member><mouse model><multidisciplinary><murine model><myocardial fibrosis><narghile><neuro-vascular><neurovascular><nicotine consumption><nicotine inhalation><nicotine use><nicotine user><novel><overexpress><overexpression><pathophysiology><preservation><pulmonary><pulmonary function><receptor><regulate BP><regulate blood pressure><salt><shisha><smoke inhalation><social role><tool><transgenic><treatment strategy><vascular constriction><vascular dysfunction><vasculopathy><vasoconstriction><water pipe><waterpipe>