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CLINICAL STUDY: WINE, NICOTINE, AND CARDIOVASCULAR DISEASE

Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats

^* Cardiology Section, Department of Medicine, V.A. San Diego Healthcare System and University of California, San Diego, California, USA

Manuscript received June 11, 2002; revised manuscript received August 5, 2002, accepted August 19, 2002.

^* Reprint requests and correspondence: Dr. Wilbur Y. W. Lew, Cardiology Section 111A, V.A. San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161 USA.
wlew{at}ucsd.edu

OBJECTIVES: Apoptosis develops in several heart diseases, but the therapeutic options are limited. It was hypothesized that nicotine, which inhibits apoptosis in several cells, inhibits cardiac apoptosis induced by lipopolysaccharide (LPS).

BACKGROUND: Over-the-counter nicotine produces sustained levels (10 to 25 ng/ml) that may be antiapoptotic. Low levels of LPS induce apoptosis by activating tissue renin-angiotensin to stimulate angiotensin II, type 1 (AT₁) receptors in cardiac myocytes.

METHODS: Adult Sprague Dawley rats were pretreated with nicotine (6 mg/kg/day) or saline for seven to ten days (miniosmotic pumps). The LPS (1 mg/kg) was injected intravenously. Toll-like receptor 4 (TLR4) and angiotensinogen messenger ribonucleic acid (mRNA) were measured in the heart after 0, 4, 8, 16, and 24 h. Cardiac apoptosis was measured by terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining after 24 h. In vitro effects of LPS (10 ng/ml, 24 h) were studied in cardiac myocytes isolated from rats pretreated with nicotine for 7 to 10 days, or after pre-exposing myocytes to nicotine (15 ng/ml) for 1, 4, 16, or 24 h.

RESULTS: Neither nicotine nor LPS affected systolic blood pressure. The LPS increased cardiac apoptosis after 24 h in saline-treated, but not nicotine-treated rats, despite similar increases in cardiac TLR4 and angiotensinogen mRNA over 8 to 16 h. The LPS-induced apoptosis was blocked by pre-exposing myocytes to nicotine for 4 to 24 h (partial inhibition after 1 h). Nicotine did not inhibit apoptosis induced by angiotensin II (100 nM, 24 h).

CONCLUSIONS: Therapeutic levels of nicotine inhibit LPS-induced cardiac apoptosis. This occurs after LPS increases TLR4 and angiotensinogen mRNA, but proximal to AT₁ receptor activation. Nicotine may be a novel inhibitor of cardiac apoptosis in conditions associated with circulating LPS (e.g., decompensated heart failure, acute and chronic infections).

Abbreviations and Acronyms   Ang II   angiotensin II   ANOVA   analysis of variance   AT1   angiotensin II receptor, type 1   cDNA   complementary deoxyribonucleic acid   LPS   lipopolysaccharide   mRNA   messenger ribonucleic acid   nAchR   nicotinic receptor for acetylcholine   RNA   ribonucleic acid   TLR4   toll-like receptor 4   TUNEL   terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling

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