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Nicotine Downregulates the Compensatory Angiotensin-Converting Enzyme 2/Angiotensin Type 2 Receptor of the Renin-Angiotensin System.

RATIONALE: Smoking is a major risk factor for the development of cardiovascular and pulmonary diseases. The importance of the renin-angiotensin system in the development of cardiovascular and pulmonary disease is well established. Angiotensin-II, by means of its type 1 receptor (angiotensin type 1 receptor, AT1 R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, inflammation, and aldosterone and vasopressin release, contributing to tissue fibrosis, endothelium dysfunction, and hypertension. Angiotensin-converting enzyme 2 cleaves angiotensin-II into the vasodilator peptide, angiotensin-(1-7), hence playing a pivotal role in the angiotensin-converting enzyme 2/angiotensin-(1-7) compensatory axis of the renin-angiotensin system. Angiotensin type 2 receptor (AT2 R), another receptor for angiotensin-II, opposes the deleterious effects of AT1 R activation, and angiotensin-converting enzyme 2-formed angiotensin-(1-7) has been shown to activate AT2 R.

OBJECTIVES: The goal of the present study was to examine how nicotine, the addictive component of cigarette smoke, alters the homeostasis of the renin-angiotensin system.

METHODS: Quantitative real-time polymerase chain reaction was performed to examine the expression of the components of the renin-angiotensin system after cigarette smoke exposure or direct nicotine inhalation. Radio telemetry was used for continuous blood pressure recording in conscious, unrestrained mice.

RESULTS: Our study showed that cigarette smoke or direct nicotine inhalation inhibits the expression of angiotensin-converting enzyme 2/AT2 R in multiple organs and cell types. In the lung, cigarette smoke (6 cigarettes/d, 12 wk) inhibited the expression of both angiotensin-converting enzyme 2 and AT2 R. In cardiac fibroblasts, nicotine exposure resulted in near complete suppression of angiotensin-converting enzyme 2 and AT2 R. In the brain, nicotine vapor inhalation inhibited angiotensin-converting enzyme 2 expression in the hypothalamus, a region involved in central regulation of cardiopulmonary function. In addition, cultured Neuro2A cells exposed to nicotine showed a dose-dependent reduction of enzymatic activity of angiotensin-converting enzyme 2. Functionally, mice exposed to nicotine vapor (12 h/d, 4 wk) exhibited significantly increased mean arterial blood pressure, which was more pronounced during the night active cycle (mean ± SE, 124 ± 0.6 mm Hg in nicotine vapor-exposed mice vs. 107 ± 0.4 mm Hg in air control mice; P < 0.0001).

CONCLUSIONS: Our findings suggest that, by downregulating the compensatory angiotensin-converting enzyme 2/AT2 R elements, nicotine disrupts the homeostasis of the renin-angiotensin system in multiple organs, which is likely an important mechanism leading to the development of cardiovascular and pulmonary disease.

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