Nicotine, cigarette smoking and cardiac function: an update

Abstract

Cigarette smoking is perhaps the unique modifiable risk factor for coronary diseases and the leading preventable cause of mortality in the United States. Although the impact of cigarette smoking on the onset and progression of atherosclerotic diseases is well established, the effect of tobacco, in particular cigarette smoking, on cardiac remodeling and contractile function is somewhat less defined. Ample evidence has shown a role for oxidative stress and interstitial fibrosis in long-term cigarette smoking-induced heart diseases with a pivotal pathological role of the main smoke component nicotine although other constituents of cigarette smoking such as carbon monoxide may also contribute to the generation of heart anomalies following cigarette smoking. This mini-review aims to summarize some of the recent findings relating to cardiac remodeling and contractile anomalies triggered by cigarette smoking, and to identify a pathophysiological mechanism through which cigarette smoking might compromise cardiac function.

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Smoking and cardiovascular health

Cardiovascular disease is the single leading cause of morbidity and mortality worldwide. An estimated 17.3 million people died from cardiovascular disease in 2008, representing 30% of all global deaths. It is expected that the mortality due to cardiovascular disease will increase to 23.3 million by 2030.¹ According to the World Health Organization (WHO), most of the cardiovascular diseases can be controlled by addressing the risk factors for cardiovascular diseases, such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood pressure, diabetes, and dyslipidemia (http://www.who.int/mediacentre/factsheets/fs317/en/index.html). Among the risk factors identified for cardiovascular diseases, cigarette smoking is perhaps the unique modifiable lifestyle factor contributing to the ever-rising cardiovascular morbidity and mortality. Smoking is considered a major independent risk factor for cardiovascular diseases including atherosclerotic vascular disease, hypertension, myocardial infarction, unstable angina, ischemia heart disease, heart failure and stroke.^2–7 According to the WHO, nearly 6 million people die each year as a direct result of smoking cigarettes (http://www.who.int/mediacentre/factsheets/fs339/en/index.html). In the United States, approximately 20.5% of adults are current smokers while smoking is responsible for 1 in every 5 deaths.⁸ The role of cigarette smoking in the overall morbidity and mortality is expected to increase by 10-fold during the 21st century.⁶ Smoking is a social behavior that has been rapidly spreading in the human population. It may start as a hobby prior to evolving into addiction, as it stimulates the central nervous system and then induces sedation.⁹ Since the number of smokers continues to rise worldwide,¹⁰ cigarette smoking-related mortality is also expected to rise at an alarming rate and warrants an immediate strategy to effectively fight against smoking-associated unfavorable impacts on human health.

Given that cardiovascular disease ranks top among all causes of deaths and that smoking is deemed a preventable health issue, the impact of cigarette smoking on cardiovascular health has drawn much attention among both physicians and scientists. The knowledge of when, to what extent, and how cigarette smoke may be involved in the onset and development of cardiovascular anomalies should help us to fight against smoking-induced morbidity and mortality.¹¹ From the group of risk factors for cardiovascular disease, smoking is causally linked to both disease onset and progression. Vascular remodeling, which is characteristic of cardiovascular disease, involves chronic inflammation and the release of various cytokines and chemokines to promote the initiation and progression of atherosclerotic lesion.¹² It has been demonstrated that short-term exposure to cigarette smoke exerts adverse effects on mitochondrial integrity and redox homeostasis, which may contribute to organ complications associated with chronic smoke exposure such as elevated blood pressure, cardiac remodeling and contractile dysfunction, impaired vascular endothelial function, increased ROS generation and a rapid decay of nitric oxide.^11,13 Nonetheless, the precise mechanism of action underlying cigarette smoking-induced cardiovascular disorders remains poorly understood, partly due to the complex mixture of cigarette smoke which contains more than 4700 different chemical compounds introducing nearly 2000 chemicals into the human bloodstream.^2,14

Nicotine in smoking-associated cardiovascular diseases

Among the massive smoke products identified, the major alkaloid present in cigarettes is nicotine, which can be detectable in the blood from chronic smokers (approximately 1–2 mg ml⁻¹).¹⁵ Nicotine is a component of smoked and chewed tobacco and represents a key component of tobacco dependence. Nicotine was first obtained as a distillate from tobacco and was employed as a prescribed drug to treat ulcer and constipation prior to its identity as a major component in cigarette smoke that promotes detrimental effects of cigarette smoking.¹⁶ Nicotine is quickly absorbed into the bloodstream through the oral cavity and lungs.^17–19 Moreover, nicotine is capable of quickly crossing the placenta to reach the embryo to accumulate in fetal blood and amniotic fluid.^17,18 Numerous studies have demonstrated a plethora of adverse effects of nicotine on adult physiology and tumorigenesis.^20–22 As one of the major toxins in cigarette smoke and smokeless tobacco, nicotine may contribute to severe oxidative stress and oxidative damage in various organs and tissues from humans.^23,24 A report from our own laboratory revealed that reduced echocardiographic contractile capacity altered the cardiomyocyte contractile and intracellular Ca²⁺ properties in murine hearts of nicotine-treated mice, the effect of which was ameliorated by the heavy metal scavenger metallothionein.²⁵ Further analysis found overt accumulation of reactive oxygen species (ROS), apoptosis and myocardial fibrosis without any change in myocardial cross-sectional area following nicotine treatment, which was mitigated by metallothionein.²⁵ Consistently, experimental evidence confirmed the development of oxidative tissue injury following chronic nicotine administration.^26,27 Earlier findings from our laboratory and others described both depressor and bradycardiac properties in the hearts in response to nicotine exposure.^28,29 Nonetheless, the precise role of nicotine in cardiovascular disease has not been definitely demonstrated.²⁰

ROS, inflammation and other possible mechanisms involved in nicotine-exerted cardiovascular responses

It is well known that cigarette smoke is a complex aerosol composed of thousands of chemical compounds. Often times, experimental data obtained from pure nicotine do not reflect the actual situation under smoke exposure. For example, a wide variety of oxidative radicals in cigarette smoke including nicotine may facilitate inflammation and oxidative stress. To this end, information obtained from nicotine on various biological responses can only provide useful but not decisive information with regard to how cigarette smoking may compromise cardiovascular health. Very recent findings from our laboratory revealed similar pathological changes in the cardiac structure and function following short-term side-stream cigarette smoke exposure in mice.⁷ These pathological changes in the heart following chronic side-stream smoke exposure (enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function, disrupted intracellular Ca²⁺ homeostasis, facilitated fibrosis, apoptosis and mitochondrial damage) were reminiscent of short-term nicotine exposure,^7,25 suggesting a unique role for nicotine in cigarette smoke exposure-induced cardiac anomalies. Meanwhile, mice treated with nicotine exhibited increased mitogenic signals and Akt phosphorylation in human lung tissues and cells from smokers, suggesting that nicotine is the major compound in cigarette smoke responsible for carcinogenesis.^30–32 A number of cell signaling pathways have been speculated in nicotine-induced biological responses. In particular, nicotine has been shown to exert its biological action through the activation of nicotinic acetylcholine receptors (nAChRs) – transmembrane ligand-gated ion channels with five subunits. Upon activation, nAChRs promote ion influx including Ca²⁺.^33,34 It has been shown that elevated intracellular Ca²⁺ interrupts intracellular signaling and organelle function.³⁵ The high density of nAChRs in bronchial and endothelial surfaces may lead to previous speculations about their pathogenic role in lung cancer and cardiovascular diseases in response to nicotine.³⁶ On the other side of the coin, nicotine may activate an inflammatory cascade resulting in the production of cytokines such as tumor necrosis factor-α (TNF-α) and potentiate chemotactic responses and oxygen radical generation by neutrophils.³⁷ In several cell types and tissues, nicotine may induce oxidative stress and apoptosis, independent from proliferative signal induction.^38–40 Exposure to cigarette smoke induces ROS production and apoptosis in rat gastric mucosa in a p53-independent manner.⁴¹ Many cells display DNA damage, genomic instability and hypomethylation of DNA in response to nicotine exposure.^38–40 Although the exact contribution of cell types to ROS generation following nicotine exposure remains somewhat elusive, there is plausible evidence suggesting a pivotal role for mitochondrial electron transport and nonphagocytic oxidases as the predominant sources of ROS generation in the heart.⁴² On the other hand, cells under long-term nicotine exposure exhibit apoptosis resistance, neoplastic transformation and tumor development.⁴³ Recent evidence further revealed that nicotine may deplete the antioxidant defense and promote oxidative stress.¹⁶ In addition to ROS production, nicotine reduces the antioxidant capacity of super-oxide dismutase (SOD) and catalase⁴⁴ and low molecular weight antioxidants such as vitamins C and E.⁴⁵ Consistently, evidence from our laboratory revealed that the heavy metal scavenger metallothionein effectively alleviated nicotine or second-hand smoke exposure-induced pathological changes such as contractile dysfunction, intracellular Ca²⁺ anomalies and interstitial fibrosis in the heart.^7,25

ROS induced by a variety compounds in tobacco may be implicated in the pathogenesis and toxicity of smoking-associated human diseases such as hypoxia, growth factor withdrawal, and heat shock.^46,47 Although the precise mechanisms underlying smoking or nicotine exposure-induced ROS production remain elusive, it may be speculated that ROS release from the mitochondria may come as a result of activation of the mitochondrial permeability pore transition.⁴⁸ Consequently, excessive levels of oxygen radicals alter cell signaling and cause damage to structural proteins, lipids and DNA, thus triggering apoptosis.^25,49 Oxidative stress is a major factor responsible for apoptosis.^9,50 Development of heart failure may be associated with a dropout of apoptotic cardiomyocytes that may develop either acutely (after ischemia–reperfusion injury) or chronically (through apoptosis).⁵¹ Therefore, regulation of apoptosis by antioxidant agents may serve as a useful maneuver to attenuate the impact of nicotine- or cigarette smoke-induced cardiac damage.^25,44,52

Conclusion

Ample epidemiological and experimental evidence supports the assertion that cigarette smoking and possibly the resulting nicotine accumulation increase the incidence of cardiac events.² The cardioprotective effect of the heavy metal scavenger metallothionein against side-stream smoke or nicotine exposure-induced changes in the cardiac geometric, contractile, and intracellular Ca²⁺ properties indicates a favorable role of antioxidants in cigarette smoking or nicotine-induced cardiovascular diseases.^7,25 Although ROS production, apoptosis and mitochondrial damage may play a role in second-hand smoking-/nicotine exposure-induced cardiac defect, the in-depth mechanism behind smoking-associated cardiovascular anomalies remains to be elucidated. Further research should focus on the interplay between cigarette smoking/nicotine exposure and cell signaling machineries responsible for mitochondrial damage, ROS production and apoptosis in an effort to better manage cigarette smoking-induced cardiovascular diseases.

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