European Heart Journal Advance Access originally published online on September 11, 2006
European Heart Journal 2006 27(19):2263-2265; doi:10.1093/eurheartj/ehl246
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Leptin and vascular function: friend or foe?
1 Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street, SW, Rochester, MN 55902, USA
2 Pfizer, Global Research and Development, Groton, CT, USA
* Corresponding author. Tel: +1 507 255 1144; fax: +1 507 255 7070. E-mail address: somers.virend{at}mayo.edu
This editorial refers to ‘Leptin is an endothelial independent vasodilator in humans with coronary artery disease: evidence for tissue specificity of leptin resistance’
by A.U. Momin et al., on page 2294
Leptin is the protein product of the adipocyte ob gene. Leptin levels are related to the amount of body fat, and leptin was viewed primarily as a modulator of appetite control and energy homeostasis. However, leptin receptors have been also identified in various peripheral tissues, including in the cardiovascular system and in human coronary arteries. Although the exact role of leptin in cardiac and vascular homeostasis is still not fully understood, most clinical studies consistently support the notion of leptin as a cardiovascular risk factor, with higher leptin levels associated with worse cardiovascular prognosis.
For example, two nested case-referent studies reported that leptin might be a risk factor for myocardial infarction and stroke.1,2 Although no association between leptin levels and coronary events was found in the Quebec Cardiovascular Study population,3 leptin was reported to be an independent predictor of coronary events (myocardial infarction or coronary revascularization) over a 5-year follow-up in the larger WOSCOPS population.4 This prospective study examined leptin's interaction with cardiovascular outcomes in moderately hypercholesterolaemic men, without a history of myocardial infarction or any other major manifestations of CAD. In addition to being predictive of outcome in the relatively low-risk WOSCOPS population, leptin was also found to have prognostic implications in higher risk patients with established and angiographically confirmed coronary atherosclerosis. Wolk et al.5 studied 382 subjects undergoing clinically indicated coronary angiography and followed up for a median of 4 years. Leptin (both unadjusted and adjusted for body mass) had a significant association with the combined endpoint of cardiac death, myocardial infarction, cerebrovascular accident, or revascularization. It is noteworthy that, both in the WOSCOPS study and in the study by Wolk et al., the positive relationship between leptin and cardiac events was independent of other recognized cardiovascular risk factors, including lipid levels and C-reactive protein (CRP). In fact, with both leptin and CRP in the model, CRP lost its predictive power, whereas leptin remained significantly related to cardiovascular outcome, lending further support to the concept that leptin is independently associated with risk for vascular events. Consistent with this notion, plasma leptin levels have been associated with the degree of coronary calcification in patients with type 2 diabetes, even after controlling for obesity and CRP.6
The specific mechanisms underlying the association between higher leptin levels and worse cardiovascular prognosis are not entirely clear. In fact, there is evidence supporting several potentially beneficial effects of leptin. In the current issue of the journal, Momin et al.7 report that leptin is an endothelium-independent vasodilator in saphenous vein and internal mammary artery vascular rings isolated from patients with CAD. These vascular effects in an isolated preparation are independent of any neurally mediated actions of leptin. They are consistent with several previous reports demonstrating leptin-induced coronary artery vasodilation in humans and activation of endothelial nitric oxide production in human aortic endothelial cells,8 effects which may arguably be cardio-protective. Leptin may also activate adult human endothelial progenitor cells9 and promote angiogenesis. Leptin may further protect against lipid accumulation and lipotoxicity, likely mediated through fatty acid oxidation by increasing expression of peroxisomal proliferation-activated receptor (PPAR)-alpha. This apparent discrepancy between the potentially protective actions of leptin, and its association with impaired cardiovascular outcome in epidemiological studies, may be reconciled by several explanations, including: first, the broad spectrum of cardiovascular actions of leptin; second, dose-dependent effects of leptin; and third, the concept of selective leptin resistance.
First, in addition to potentially beneficial actions of leptin on vasculature, leptin can elicit changes that may be detrimental to cardiovascular health. These include sympathetic activation, pressor responses, insulin resistance, enhanced platelet aggregation, impaired fibrinolysis, generation of reactive oxygen species, pro-inflammatory effects (including the association of plasma leptin with CRP),10 hypertrophy and proliferation of vascular smooth muscle cells, downregulation of PPAR-gamma in macrophages and foam cells, upregulation of endothelin-1 production in vascular cells, and paraoxonase-reducing effects. Therefore, it is likely the balance between the potentially detrimental and beneficial actions of leptin, rather than any single action alone, that may explain the relationship between leptin and prognosis (Figure 1).
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Second, the relationship between leptin and prognosis appears to be non-linear5 so that an initial increase in cardiovascular risk with increasing leptin levels is followed by a plateau phase, after which the risk increases further when leptin concentrations exceed a certain level. Similarly, in the WOSCOPS study,4 with leptin levels divided into quintiles, cardiovascular risk was not increased in the second and third quintiles, but increased significantly in the fourth and fifth quintiles, without any difference between the highest two quintiles. This apparent ‘threshold effect’ may be related to differential interactions between the beneficial and detrimental effects of leptin, at different leptin levels. Dose-dependence may be evident even in specific actions of leptin. For example, we have demonstrated that leptin, at a physiological concentration of 10 ng/mL, significantly increases tube formation by human endothelial progenitor cells, but at a higher concentration of 100 ng/mL tube formation is reduced, together with inhibition of cell migration.9 Similar concentration-dependent effects of leptin have been reported in various cell types with regard to potential mediators of the effects of leptin, such as VEGF, nitric oxide, endothelin-1, reactive oxygen species, HUVEC cell proliferation, and intracellular signalling pathways (p38 MAPK and ERK1/2 MAPK phosphorylation). These observations suggest that leptin exerts non-linear dose-dependent effects, which may have important implications for understanding its physiological vs. pathophysiological actions.
Finally, part of the imbalance between the beneficial and detrimental effects of leptin may be related to the phenomenon of selective leptin resistance, especially in obese individuals. Leptin suppresses appetite and increases energy expenditure, hence inducing weight loss. Obese individuals have high leptin levels, but their obesity persists because of a presumed resistance to the appetite suppressant and metabolic effects of leptin (‘leptin resistance’). Recent studies suggest that there is preservation of several peripheral effects of leptin (sympathoexcitation, platelet activation, and so on) despite resistance to the satiety and weight-reducing actions of leptin, particularly at elevated leptin levels. Momin et al. address this question indirectly in their analysis, but specific actions of leptin (including the beneficial vs. the detrimental effects) which are susceptible to the phenomenon of leptin resistance in obesity remain to be defined.
Although Momin and colleagues provide important new information regarding the direct vascular effects of leptin in humans, some limitations of the experimental model have to be recognized in view of the complex cardiovascular effects of leptin. These include the ‘ex vivo’ nature of the experiments. There is a clear need for ‘in vivo’ studies that would take into account all the local (direct and indirect), humoral, and autonomic influences of leptin, such that its true ‘in vivo’ effects on vascular homeostasis are better clarified. Furthermore, it is important to study a range of clinically relevant leptin concentrations, in healthy vs. diseased vessels, in several different disease conditions, and in the presence and absence of relevant medications. Synergies and redundancies of leptin's individual actions, and the integrated physiological and/or pathophysiological consequences, await identification before leptin can be used in cardiovascular risk stratification, and before beneficial or detrimental cardiovascular implications of any interventions affecting leptin levels are understood.
Acknowledgements
V.K.S. is supported by NIH grants, HL-65176, HL-70302, HL-73211, and M01-RR00585.
Conflict of interest: RW and VKS have intellectual property with Mayo Medical Ventures relevant to leptin.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi831 
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[Abstract/Free Full Text]
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