| COMMENTARIES |
Visfatin - Another Target to Reduce Cardiovascular Risk?
Michael S. Kostapanos, M.D. and Haralampos J. Milionis, M.D., Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
Please address correspondence to:
Haralampos Milionis, M.D.
Assistant Professor of Internal Medicine
Department of Internal Medicine
School of Medicine, University of Ioannina
451 10 Ioannina
Greecce
Tel: (+30) 2651097516
Fax: (+30) 2651097016
Email: hmilioni@uoi.gr
Introduction
Visfatin is a novel adipokine secreted mostly by adipose tissue, while ubiquitously present in many other tissues such as the liver, muscles, and human bone marrow [1]. Increased visfatin expression or levels have been identified in a variety of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as in acute processes such as acute lung injury, sepsis, and amnionitis [2]. Recent evidence suggests that visfatin is associated with several cardiovascular risk factors and may have a role in the pathogenesis of atherosclerosis.
Associations of Visfatin with Cardiovascular Risk Factors
Visfatin has been described to exhibit insulin-like activity by exerting a great affinity to the insulin receptor [3]. This observation led to expectations that visfatin may serve as a promising therapeutic option for the management of type 2 diabetes or insulin resistance syndromes, such as the metabolic syndrome. However, the insulin-mimetic activity of visfatin has not been widely confirmed. On the contrary, the majority of studies showed that patients with impaired glucose metabolism, such as those with type 2 diabetes mellitus or with the metabolic syndrome, may have higher plasma visfatin levels as compared to healthy controls. Additionally, data from our group indicate that plasma visfatin levels correlate with most of the components of the metabolic syndrome [4].
To date, it remains unclear whether higher plasma visfatin levels in type 2 diabetes or in insulin resistant syndromes are associated with insulin resistance itself or with a greater amount of visceral adipose tissue observed in those subjects. In this context, it has been noted that plasma visfatin levels are higher in obese subjects as compared to non-obese ones. Of interest, male obese subjects exhibit higher plasma visfatin levels compared with females [5]. This observation may imply an association between central type obesity in parallel with visceral adipose tissue accumulation, mostly observed in men, and higher plasma visfatin concentrations.
Circulating plasma visfatin levels have been found to be related with various plasma lipoproteins, including total cholesterol, low density lipoprotein cholesterol, and triglyceride levels [4]. There is little evidence suggesting a potential association of visfatin circulating levels with the levels of the systolic or diastolic blood pressure [4,6].
A reverse correlation of plasma visfatin levels with estimates of renal function, as reflected by determinations of glomerular filtration rate and creatinine clearance, and positive correlation with proteinuria, mainly albumin, has been reported [7]. Patients with chronic kidney disease were found to have higher circulating visfatin levels as compared to healthy controls, while patients at severe stages of renal function impairment may have higher plasma visfatin levels as compared to those at moderate or mild renal failure [7].
Visfatin: a Role in Atherosclerosis
Increased plasma visfatin levels have been reported in patients with carotid atherosclerosis and the metabolic syndrome, and were independently associated with the maximum carotid intima media thickness (CIMT) [8]. An association of plasma visfatin levels with impaired flow-mediated endothelial-dependent dilatation of the renal vasculature has been shown in patients with type 2 diabetes mellitus [7].
A visfatin-provoked increase in markers of vascular oxidative stress, such as the production of reactive oxygen species, which are known to associate with an impairment of the nitric oxide-dependent endothelial function, could confer as a potential mechanism to explain the dysfunction of vascular endothelium induced by this adipokine. A potential pro-inflammatory activity has also been ascribed to visfatin. Studies in cultures of human leukocytes (in vitro) showed that visfatin may increase the expression of various inflammatory mediators known to be involved in the pathogenesis of atherosclerosis, such as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha [8]. Visfatin may increase inflammatory cell adhesion to the aortic endothelium by an adipokine-provoked induction of several cell adhesion molecules, such as VCAM-1 [9].
Besides its role in atherogenesis, visfatin has been reported to contribute to the destabilization process of atherosclerotic lesions [8]. In vitro, visfatin increases the activity of matrix metalloproteinase (MMP)-9, which is known to contribute to atherosclerotic plaque destabilization, in THP-1 monocytes [8]. Among patients with established coronary artery disease, there was a strong visfatin immunostaining in lipid-rich regions within the material obtained at sites of plaque rupture in patients with acute myocardial infarction [8].
On the whole, visfatin may be regarded as an inflammatory mediator, localized to foam cell macrophages within unstable atherosclerotic lesions and may potentially play a role in the destabilization of atherosclerotic plaques and subsequently the occurrence of cardiovascular events.
Effect of Various Therapeutic Interventions on Visfatin
Over the recent few years there is increasing interest regarding the effects of diverse therapeutic strategies on plasma visfatin levels, including lifestyle interventions, such as exercise and low-calorie diet.
There is a great body of contrasting evidence concerning the effect of thiazolidinediones on plasma visfatin, which showed either a neutral or a raising effect on visfatin concentrations. Metformin seems to exert no effect on visfatin levels or expression; however there is a single experimental study that showed that the newly marketed exenatide may decrease visfatin concentration in high-calorie-fed rats.
Sibutramine, but not orlistat, has been reported to produce a drop in plasma visfatin levels [10,11]. Various studies failed to reach safe conclusions concerning the effect of various surgical anti-obesity interventions on visfatin concentrations. Antihypertensive medications, including verapamil slow release in combination with trandolapril given along with sibutramine, may exert a favorable lowering effect on plasma visfatin levels [11].
There is a heterogeneity concerning the effects of different lipid-modulating regimens on plasma visfatin levels. Fibrates, fenofibrate in particular, seem not to alter plasma visfatin levels. The effect of statin therapy on visfatin expression and plasma levels remains unclear. Evidence from one in vitro study suggested that atorvastatin may decrease visfatin expression in differentiated white adipocytes [12]. This action was paralleled by the acute inhibition of insulin-induced glucose uptake in those cells.
Rosuvastatin 10 mg/day has been shown to induce a small, though significant decrease in plasma visfatin levels in patients with primary hyperlipidemia [13]. This effect was not associated with the lipid-lowering capacity of the drug, suggesting a novel lipid-independent (pleiotropic) antiatherogenic action. In contrast to rosuvastatin, simvastatin treatment in non-diabetic patients at high cardiovascular risk either alone or in combination with pioglitazone had no effect on plasma visfatin levels [14]. Whether the mevalonate pathway inhibitory effect of statins may contribute to the visfatin-lowering potential of the class remains to be clarified. The effects of statin therapy on this novel adipokine need to be further tested in larger studies with the use of different agents and various dosage regimens both in primary prevention as well as in patients with established atherosclerotic cardiovascular disease.
References