1. Introduction
Cardiovascular diseases cause 3% of all deaths in North America being the most common cause of death in European men under 65 years of age and the second most common cause in women. These facts suggested us to consider new strategies for prediction, prevention, and treatment of cardiovascular disease [1]. Inflammatory mechanisms play a central role in the pathogenesis of atherosclerosis and its complications [2]. It has been demonstrated that atherogenic lipoproteins such as apo(B-100), oxidized low-density lipoprotein (LDL), remnant lipoprotein (beta-VLDL), and lipoprotein(a) play a critical role in the proinflammatory reaction. High-density lipoprotein (HDL) is antiatherogenic lipoproteins that exert anti-inflammatory functions [3–5]. Plasma LDL cholesterol is a well-established predictor of coronary artery disease (CAD), and many observations have pointed out that Lp(a) and apolipoprotein(a) (apo(a)) levels may be risk factors for cardiovascular diseases (CVD) [6–8].
2. Native Lp(a)
Lp(a) is an LDL-like molecule consisting of an apolipoprotein B-100 (apo(B-100)) particle attached by a disulphide bridge to apo(a). Lp(a) plasma concentrations are controlled by the apo(a) gene located on chromosome 6q26-27 [9]. The unique character of Lp(a) is based on the apo(a) highly glycosylated protein structurally homologous to plasminogen [10].
Because of the structural homology with plasminogen, Lp(a) might have important antithrombolytic properties, which could contribute to the pathogenesis of atherothrombotic disease. For example, Lp(a) binding to immobilised fibrinogen and fibrin results in the inhibition of plasminogen binding to these substrates [24, 25]. In addition, Lp(a) competes with plasminogen for its receptors on endothelial cells, leading to diminished plasmin formation, thereby delaying clot lysis and favouring thrombosis. The high affinity of Lp(a) for fibrin provides a mechanistic basis for their frequent colocalization in atherosclerotic plaques [26, 27]. Moreover Lp(a) induces the monocyte chemoattractant (CC chemokine I-309), which leads to the recruitment of mononuclear phagocytes to the vascular wall [28, 29].
3. Oxidized Lp(a)
Lp(a) particles can suffer oxidative modification and scavenger receptor uptake, with cholesterol accumulation and foam cell formation [30], leading to atherogenesis.
Some studies showed that Lp(a) particles are prone to oxidation and that the increased risk of coronary artery disease associated with elevated Lp(a) levels may be related in part to their oxidative modification and uptake by macrophages, resulting in the formation of macrophage-derived foam cells [31].
Lp(a) particles are susceptible to oxidative modification and scavenger receptor uptake, leading to intracellular cholesterol accumulation and foam cell formation, which contributes further to atherogenesis [25, 32].
4. Glycated Lp(a)
Nonenzymatic glycation of lipoprotein may contribute to the premature atherogenesis in patients with diabetes mellitus by diverting lipoprotein catabolism from nonatherogenic to atherogenic pathways. It has been observed that the proportion of apo (B-100) in glycated form was significantly higher in diabetic patients than in nondiabetic controls, and equally that plasma Lp(a) levels might be increased in diabetic patients [36].
5. Atherogenic and Proinflammatory Mechanisms of Lp(a)
5.1. Lp(a) and Endothelial Dysfunction
As the atherosclerotic plaque progresses, growth factors and cytokines secreted by macrophages and foam cells in the plaque stimulate vascular smooth muscle cell growth and interstitial collagen synthesis [37]. Moreover, the apo(a) component of Lp(a) has been shown to enhance the expression of ICAM-1 [13]. Thus, these effects on endothelial cell function may provide mechanisms by which Lp(a) contributes to the development of atherosclerotic lesions. Reduction in nitric oxide (NO) availability also initiates the activation of matrix metalloproteinases MMP-2 and MMP-9 [38, 39], and further it reduces inhibition of platelet aggregation [40]. Thus, endothelial dysfunction with reduced NO bioavailability, increased oxidant excess, and expression of adhesion molecules contributes not only to initiation but also to progression of atherosclerotic plaque formation and triggering of cardiovascular events.
5.2. Inflammation, Atherosclerosis, and Lp(a)
Lp(a) may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques [47]. Lp(a) may lead to an inflammatory process by inducing the expression of adhesion molecules on endothelial cells, the chemotaxis of monocytes, and the proliferation of smooth muscle cells [48]. Moreover Lp(a) can augment the production of cytokines by vascular cells, and through the autocrine and paracrine mechanisms, the inflammatory reaction may lead to a vicious cycle resulting in lesion progression [49]. Lp(a) acts on the fibrinolytic system in several ways which include the inhibition of plasminogen binding and activation, thereby impairing fibrinolytic activity and the dissolution of thrombi. High concentrations of Lp(a) might increase the risk of thrombus formation by impeding fibrinolytic mechanisms in the region of the plaque.
7. Conclusions
The clinical interest in Lp(a) is largely derived from its role as a cardiovascular risk factor. Although not considered an established risk factor, Lp(a) levels have been associated with cardiovascular disease in numerous studies [72, 104, 105]. Recently Lp(a) serum levels were found to be associated with the severity of aortic atherosclerosis, especially in abdominal aorta, as well as coronary atherosclerosis [106]. Moreover a study by Momiyama et al. [107] demonstrated that elevated Lp(a) has incremental prognostic value in symptomatic patients with coronary artery revascularization [108]. Lp(a) is involved in the development of atherothrombosis and activation of acute inflammation exerting a proatherogenic and hypofibrinolytic effect. Lp(a) plays a critical role in the proinflammatory reaction and can be considered as a common joint among different metabolic systems. Other actions of Lp(a) can be resumed as follows: inhibition of the activation of plasminogen; inhibition of the activation of TGF-β; activation of acute inflammation; induction of the expression of adhesion molecules; elevation of the production of cytokines. Moreover Lp(a) is implicated in the activation of endothelial uptake, oxidative modification, and foam cell formation, suggesting that these processes could play an important role in atherosclerosis. Recent findings suggest that Lp(a)-lowering therapy might be beneficial, at least in some subgroups of patients with high Lp(a) levels. A possible future therapeutic approach could include apheresis in high-risk patients with already maximally reduced LDL cholesterol levels in order to reduce major coronary events [72]. However, further studies are needed to define such subgroups with regard to Lp(a) levels, apo(a) size, and the presence of other risk factors.
Referência :
(1) Biomed Res Int. 2013;2013:650989.