Lipoprotein(a) as a Potential Causal Genetic Risk Factor of Cardiovascular Disease A Rationale for Increased Efforts to Understand its Pathophysiology and Develop Targeted Therapies
ABSTRACT Recent published studies have provided increasing evidence that lipoprotein(a) [Lp(a)] may be a potential causal, genetic, independent risk factor for cardiovascular disease (CVD). Lp(a) levels >25 mg/dl are present in ∼30% of Caucasians and 60% to 70% of Blacks. Lp(a) is composed of apolipoprotein B-100 and apolipoprotein (a) [(apo(a)]. Circulating Lp(a) levels are primarily influenced by the LPA gene without significant dietary or environmental effects, mediating CVD risk throughout the patient's lifetime. Recent clinical outcomes studies, meta-analyses, and Mendelian randomization studies, in which randomization of Lp(a) levels is achieved through the random assortment of LPA gene variants thereby removing confounders, have shown that genetically determined Lp(a) levels are continuously and linearly related to risk of CVD. Currently, Lp(a) pathophysiology is not fully understood, and specifically targeted therapies to lower Lp(a) are not available. We provide a rationale for increased basic and clinical investigational efforts to further understand Lp(a) pathophysiology and assess whether reducing Lp(a) levels minimizes CVD risk. First, a detailed understanding of Lp(a) synthesis and clearance has not been realized. Second, several mechanisms of atherogenicity are known to varying extent, but the relative contributions of each are not known. Lp(a) may be atherothrombotic through its low-density lipoprotein moiety, but also through apo(a), including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids, and antifibrinolytic effects. Finally, development of specific Lp(a)-lowering agents to potently lower Lp(a) will allow testing of mechanistic hypotheses in animal models and the design of randomized clinical trials to assess reduction in CVD. A convergence of academic, scientific, pharmaceutical, and National Institutes of Health priorities and efforts can make this a reality in the next decade.
- Current opinion in lipidology 12/2012; 23(6):591-2. DOI:10.1097/MOL.0b013e328359f162 · 5.80 Impact Factor
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ABSTRACT: Background: Lipoprotein(a) is associated with cardiovascular disease risk. This may be attributable to the ability of lipoprotein(a) to elicit endothelial dysfunction. We previously reported that apolipoprotein(a) (the distinguishing kringle-containing component of lipoprotein(a)) elicits cytoskeletal rearrangements in vascular endothelial cells resulting in increased cellular permeability. These effects require a strong lysine-binding site (LBS) in apo(a).Methods and Results: We now report that apo(a) induces both nuclear β-catenin-mediated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE(2)) secretion, indicating a proinflammatory role for Lp(a). Apo(a) caused the disruption of VE-cadherin/β-catenin complexes in a Src-dependent manner, decreased β-catenin phosphorylation, and increased phosphorylation of Akt and GSK-3β, ultimately resulting in increased nuclear translocation of β-catenin; all these effects are downstream of apo(a) attenuation of PTEN activity. The β-catenin-mediated effects of apo(a) on COX-2 expression were absent using a mutant apo(a) lacking the strong LBS. Interesting, the normal and LBS mutant forms of apo(a) bound to HUVECs in a similar manner and the binding of neither was affected by lysine analogues.Conclusions: Together our findings suggest a novel mechanism by which apo(a) can induce proinflammatory and proatherosclerotic effects through modulation of vascular EC function.Molecular biology of the cell 12/2012; DOI:10.1091/mbc.E12-08-0637 · 5.98 Impact Factor
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ABSTRACT: Lipoprotein(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). Many observations have pointed out that Lp(a) levels may be a risk factor for cardiovascular diseases. Lp(a) inhibits the activation of transforming growth factor (TGF) and contributes to the growth of arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells and the migration of smooth muscle cells to endothelial cells. Moreover Lp(a) inhibits plasminogen binding to the surfaces of endothelial cells and decreases the activity of fibrin-dependent tissue-type plasminogen activator. Lp(a) may act as a proinflammatory mediator that augments the lesion formation in atherosclerotic plaques. Elevated serum Lp(a) is an independent predictor of coronary artery disease and myocardial infarction. Furthermore, Lp(a) levels should be a marker of restenosis after percutaneous transluminal coronary angioplasty, saphenous vein bypass graft atherosclerosis, and accelerated coronary atherosclerosis of cardiac transplantation. Finally, the possibility that Lp(a) may be a risk factor for ischemic stroke has been assessed in several studies. Recent findings suggest that Lp(a)-lowering therapy might be beneficial in patients with high Lp(a) levels. A future therapeutic approach could include apheresis in high-risk patients in order to reduce major coronary events.01/2013; 2013:650989. DOI:10.1155/2013/650989