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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD Leptin has been shown to increase sympathetic nerve activity, stimulate generation of reactive oxygen species, upregulate endothelin-1 production and potentiate platelet aggregation. Leptin and Cardiovascular Diseases by Jian-Dong Luo, Gen-Shui Zhang and Min-Sheng Chen Summary Although obesity is strongly associated with cardiovascular disease (CVD), the endogenous relationship between obesity and CVD is still not fully clear. Emerging evidence from both animal and human studies indicates that leptin may play an important role in obesity-related CVD. Besides modulating appetite and metabolism, leptin has also been shown to increase sympathetic nerve activity, stimulate generation of reactive oxygen species, upregulate endothelin-1 production and potentiate platelet aggregation. These effects of leptin may contribute to hypertension, endothelial dysfunction and atherosclerosis in obese individuals. Better understanding the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. These recent discoveries could lead to novel strategies for treatment of obesity-associated CVD. © 2005 Prous Science. All rights reserved. Obesity is a chronic metabolic disorder with important public health implications, affecting not only developed but also developing countries. In the United States, the overweight and obese adult popula-tion now exceeds 60%, and there has been a two- to fourfold increase in children overweight and obese over the last 30 years.1 Overweight or obese individuals experience greatly elevated morbidity and mortality from nearly all of the common cardiovascular diseases such as stroke, coronary heart disease, congestive heart failure, cardiomyopathy and possibly arrhythmia/sudden death.2,3 Because primary treatment and prevention of obesity often fail or are only partially successful, it is anticipated that the future will bring ever-increasing demands to treat the cardiovascular conditions attri-butable to obesity. Therefore, understanding the basic biology of obesity-related cardiovascular diseases and disorders has become ever more important. In obese individuals, activation of the sympathetic nervous system and impairment of endothelial function have generally been thought to be the two pivotal phenotypical traits known to be associated with obesity-related cardiovascular diseases.47 However, the mechanisms responsible for these dysfunctions in obesity have not yet been clearly elucidated. Since the discovery that the adipocyte ob gene encodes leptin, a secreted protein that regulates body weight in mice and is increased in plasma with obesity,8,9 there has been intense interest in its potential roles in obesity-related cardiovascular diseases. Although it is an important action of leptin on the central nervous system (CNS) to maintain energy balance, likely through increasing sympathetic nervous tone, the localization of leptin receptors in a wide range of tissues has suggested that leptin may play physiological and pathophysiological roles through binding to central as well as peripheral receptors. Evidence is emerging for an important role of leptin in obesity-related cardiovascular diseases. In this review, we summarize the current understandings of the relationship between leptin and cardiovascular diseases. Leptin and cardiovascular diseases It is well established that uncorrected obesity dramatically increases morbidity and mortality of cardiovascular diseases.2,3,1012 However, the intrinsic links between obesity and cardiovascular diseases are still unclear. Accumulating evidence from both animal and human studies indicates that elevated leptin is an important factor that may contribute to cardiovascular diseases in obese individuals.1320 Clinical studies have shown that leptin concentrations rise exponentially with increasing percentage body fat, and obese individuals have significantly increased leptin production.2123 Similarly, data from different populations suggest strong positive correlations between elevated leptin and hypertension.23,24 These results from clinical researches are supported by animal studies that indicate that infusions of leptin cause a slow rise in arterial pressure after 3 to 5 days in rats.25,26 More importantly, transgenic animal studies show that blood pressure in ob/ob obese mice, in which plasma leptin levels are not detectable, is normal, whereas obese transgenic mice overexpressing leptin are more prone to develop hypertension than wild-type animals.27,28 These results from transgenic animal studies further confirm hypertensive effects of leptin. In addition to hypertensive effects, elevated leptin levels seem to correlate with atherosclerosis, since animal studies have shown that ob/ob obese mice, which lack a functioning leptin gene, fail to develop atherosclerosis in an aorta as would be expected in obese individuals after fed high-cholesterol chow for up to 4 months.29,30 In patients with angiographically confirmed coronary atherosclerosis, leptin is a novel predictor of future cardiovascular events independent of other risk factors, including lipid status and C-reactive protein.31 Moreover, the West of Scotland Coronary Prevention Study also indicated that higher plasma leptin concentrations in hypercholesterolemic men are associated with an increased risk of a future coronary event.32 Finally, Paolisso et al. also showed that plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men.33 Collectively, the above data suggest that elevated leptin in obese individuals is an important risk factor associated with obesity-related cardiovascular diseases (Fig. 1).
Fig. 1. The possible mechanisms of leptin inducing cardiovascular disease. Possible mechanisms underlying leptin inducing cardiovascular diseases Sympathetic nervous system activation Activation of the sympathetic nervous system is an important feature of obesity in humans and in animal models. Emerging evidence has highlighted the pivotal role of enhanced sympathetic activity in obesity-hypertension.5,3436 Long-term overactivity of the sympathetic nervous system could increase arterial pressure by causing peripheral vasoconstriction and by augmenting renal tubular sodium reabsorption. Investigation of regional sympathetic nerve activity in obese humans using norepinephrine spillover has shown that obesity is linked to increased sympathetic activity to the kidney, a key organ of the cardiovascular homeostasis.37 In-creased renal sympathetic nerve activity was also proved in animal models of dietary obesity.38 Recent evidence indicates that leptin may represent a link between excess adiposity and increased cardiovascular sympathetic activity. Besides its effect on appetite and metabolism, leptin acts in the hypothalamus to increase blood pressure through activation of the sympathetic nervous system.39 Collectively, these data suggest that leptin may be an important cause of cardiovascular sympathoactivation associated with obesity in humans. Endothelial dysfunction Endothelial dysfunction such as reduced nitric oxide responsiveness is a common abnormality in obesity.40,41 Damage of the endothelium is an important risk factor for cardiovascular diseases, since it leads to decreases of vasodilation function. Although mechanisms linking obesity with endothelial dysfunction have not yet been completely clarified, recent investigations suggested that elevated leptin may be an important factor that contributes to this abnormality. First, Quehenberger and colleagues indicated that high- and low-affinity leptin binding sites on human umbilical vein endothelial cells (HUVECs) mediate a time- and dose-dependent increase of endothelin-1 (ET-1) mRNA expression and protein secretion after incubation of HUVECs with leptin. Leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. This investigation definitely shows that leptin is able to stimulate ET-1 human umbilical vein endothelial production in cells.15 Several studies have also shown that there are increased ET-1 levels in obese subjects42,43 and enhanced vascular production of ET-1 in hypertensive patients with increased body mass has been suggested as a potential mechanism for endothelial dysfunction.44 Blockade of the endothelin A (ETA) receptors induces significant vasodilation in overweight and obese humans but not in lean hypertensive subjects. These results indicate a selective enhancement of ETA receptor-dependent vasoconstrictor tone in obese hypertensive patients, and elevated leptin levels may contribute to increased ET-1 levels in obese individuals. Secondly, oxidative stress may be another possible mechanism responsible for endothelial dysfunction in obese individuals, since there is significant systemic oxidative stress,4546 and oxidative stress can decrease nitric oxide bioactivity. Several studies have shown that leptin induces oxidative stress in endothelial cells and cardiomyocytes, which suggests that elevated leptin levels may be an important contributor responsible for oxidative stress in obesity. It should be noticed that leptin has opposing effects on endothelial function. Leptin has been shown to increase nitric oxide release from endothelial cells in vitro.47 When infused into leptin-deficient ob/ob mice, leptin enhances endothelium-dependent vasodilation ex vivo. The release of leptin by adipocytes may cause a local nitric oxide-mediated vasodilation in fatty tissue that enhances lipid metabolism.48 How-ever, it is important to note here that the acute effects of leptin may be quite different from long-term elevations of leptin, since leptin is known to increase oxidative stress in endothelial cells. The long-term consequences of oxidative stress may include reductions in nitric oxide bioactivity and/or synthesis and an increase in the expression of adhesion molecules and chemokines that mediate vascular inflammation and atherogenesis. Prothrombotic effects Recent studies provide evidence for a direct link between leptin and the risk for thrombotic complications in obese individuals.19,20,49 For example, although arterial injury provokes thrombosis in both lean and obese (ob/ob) mice, the time to complete thrombotic occlusion is significantly delayed in the ob/ob mice, and the thrombi formed are unstable and frequently embolize. The ob/ob mice lack leptin, and intraperitoneal administration of leptin to these mice before injury restores the phenotype of lean mice by shortening the time to occlusion, stabilizing the thrombi and decreasing the patency rate.19,20 Similarly, the wild-type mice that were treated with a leptin-neutralizing antibody before carotid artery injury with ferric chloride demonstrated prolonged times to thrombotic occlusion and formed unstable, embolizing thrombi.49 Platelets express the leptin receptor, and leptin potentiates the aggregation of platelets from ob/ob but not db/db mice in response to known agonists. These results reveal a novel receptor-dependent effect of leptin on platelet function and hemostasis and suggest that endogenous leptin may regulate arterial and venous thrombosis in vivo. Inhibition of circulating leptin may protect against arterial and venous thrombosis in hyperleptinemic obese individuals and provide new insights into the molecular basis of cardiovascular complications in obese individuals. The results also suggest that these prothrombotic properties should be considered when developing therapeutic strategies based on leptin. Cardiovascular remodeling Several studies have provided new insights regarding leptin inducing cardiovascular remodeling. Schafer et al.50 indicated that wild-type mice with hyperleptinemia caused by a high-fat diet showed a significantly enhanced neointimal and medial thickening of the vascular wall after induction of carotid artery injury with ferric chloride. In contrast, leptin-deficient (ob/ob) mice on a high-fat diet did not show increased lesion formation, despite an increase in body weight, glucose and lipid levels. Daily leptin treatment of (ob/ob) mice resulted in a significantly increased lesion formation independent of the concomitant diet, whereas treatment of leptin receptor-deficient (db/db) mice with leptin did not alter vascular lesion progression, suggesting a direct, receptor-mediated effect of leptin on the vascular wall. Cell culture experiments and analysis of vascular smooth muscle cells within the neointima suggest a growth-stimulating effect of leptin on vascular smooth muscle cells. In concert with these findings, Stephenson et al. demonstrated that neointima formation after vascular injury was reduced in leptin receptor mutant mice.51 Evidence of an important role of leptin in restenosis in a clinical setting comes from the recently published results from Piatti et al., who investigated restenosis in 120 patients with insulin resistance and concomitant coronary heart disease undergoing coronary stenting.52 Increased leptin and insulin levels were associated with a higher incidence of in-stent restenosis. Except modulating effects on vascular tissue growth, leptin also affects cardiomyocyte growth. Our results53 have indicated that leptin elevates ET-1 and reactive oxygen species levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. All of the effects of leptin on cardiomyocytes were significantly inhibited by a selective ETA receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. Another study also showed that leptin induces cardiomyocyte hypertrophy through P38 pathway activation.54 These results suggest a direct hypertrophic effect of leptin and may offer a biological link between hypertrophy and hyperleptinemic conditions such as obesity. Selective leptin resistance In obese humans, leptin resistance, which is associated with hyperleptinemia, is much more common than leptin deficiency.55 The question is if obese individuals are leptin-resistant, how can leptin contribute to cardiovascular diseases. Recent studies have shown that there is preservation of the sympathoexcitatory actions of leptin despite resistance to the satiety and weight-reducing actions of the hormone in agouti yellow obese mice.56,57 Selective leptin resistance might explain how hyperleptinemia could contribute to cardiovascular diseases in obese states, where there is resistance to the metabolic actions of leptin. It is speculated here that this concept may have potential implications for human obesity, which is often associated with elevated plasma leptin and partial resistance to the satiety effects of leptin. If selective leptin resistance occurs in obese humans, then leptin could contribute to cardiovascular diseases, despite resistance to its metabolic actions. The mechanism(s) of selective leptin resistance is not fully elucidated. In obese mice, the inability of leptin to activate leptin-signaling pathways such as STAT3 proteins appears to be restricted to the arcuate nucleus of the hypothalamus.58 Leptin-induced increases in renal sympathetic activity and blood pressure are mediated by the ventromedial and dorsomedial hypothalamus.59 Therefore, selectivity in leptin resistance may be attributable to the inability of leptin to activate downstream signaling pathways in the arcuate nucleus but preservation of leptin action in other cardiovascular-related hypothalamic areas. The selectivity in leptin resistance may also relate to the divergent signaling pathways downstream from the leptin receptor. Phosphoinositol-3 kinase is an important intracellular signaling pathway in the control of renal sympathetic outflow by leptin because renal sympathoactivation to leptin is prevented by inhibition of this enzyme.60 Another possible mechanism for selective leptin resistance may be involved in different leptin receptor isoforms. Several isoforms (af) of the leptin receptor (Ob-R) exist as a result of alternative mRNA splicing. Leptin-resistant db/db mice lack the long isoform of the Ob-R (Ob-Rb) that has a cytoplasmic domain required for activation of signal transducers and activators of transcription. The other short isoforms (Ob-Ra, Ob-Rc, Ob-Rd, Ob-Re) exhibit abbreviated intracellular amino acid sequences and have little intracellular signaling capacity.61 Their physiological role is less clear. However, a recent study has shown that a short form of leptin receptor performs signal transduction in CHO cells.62 Another study suggested that there existed short isoform Ob-Ra mRNA, but not long isoform Ob-Rb mRNA, in cultured neonatal rat cardiomyocytes.54 Leptin stimulated the mitogen-activated protein kinase (MAPK) P38 and P42/44 and induced hypertrophic effects in cultured cardiomyocytes. Therefore, selective leptin resistance may be involved in different isoforms of leptin receptors, mediating different effects in different tissues. Acknowledgments J.-D. Luo is supported by a grant from the Ministry of Education (No. 0110-B042), Peoples Republic of China. M.-S. Chen is supported by a grant from the National Natural Science Foundation (No. 30440053), Peoples Republic of China. References 1. -Eckel, R.H., Barouch, W.W. and Ershow, A.G. 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J Biol Chem 1977, 272: 3268695. 62. -Murakami, T., Yamashita, T., Iida, M. et al. A short form of leptin receptor performs signal transduction. Biochem Biophys Res Commun 1997, 231: 269. Jian-Dong Luo* is Professor and Gen-Shui Zhang is Lecturer in the Department of Pharmacology and Min-Sheng Chen* is Professor in the Department of Internal Medicine, Guangzhou Medical College, Guangzhou, China. *Correspondence: Jian-Dong Luo, M.D., Ph.D., Department of Pharmacology, Guangzhou Medical College Guangzhou, China 510182. Tel: 8620-8134-0203; Fax: 8620-8134-0137; E-mail: jiandong-luo@hotmail.com; or Min-Sheng Chen, M.D., Department of Internal Medicine, Guangzhou Medical College, Guangzhou, China 510182. Tel: 8620-81340633; Fax: 8620-8134-0448; E-mail: gzminsheng@vip.163.com. Drug News & Perspectives
Vol. 18, No. 7, 2005, pp. 427-431
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