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1.
Curr Opin Lipidol ; 30(6): 428-437, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31577611

RESUMO

PURPOSE OF REVIEW: Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue. RECENT FINDINGS: Although the ability of PCSK9i to lower Lp(a) by 15-30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated. SUMMARY: Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.

2.
J Lipid Res ; 60(12): 2082-2089, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31551368

RESUMO

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.

3.
J Clin Lipidol ; 13(3): 374-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31147269

RESUMO

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

4.
J Am Coll Cardiol ; 73(17): 2150-2162, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31047003

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention. OBJECTIVES: This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations. METHODS: This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells. RESULTS: Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL. CONCLUSIONS: In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.

5.
Trends Pharmacol Sci ; 40(3): 212-225, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30732864

RESUMO

Interest in lipoprotein (a) [Lp(a)] has exploded over the past decade with the emergence of genetic and epidemiological studies pinpointing elevated levels of this unique lipoprotein as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). This review summarizes the most recent discoveries regarding therapeutic approaches to lower Lp(a) and presents these findings in the context of an emerging, although far from complete, understanding of the biosynthesis and catabolism of Lp(a). Application of Lp(a)-specific lowering agents to outcome trials will be the key to opening this new frontier in the battle against CVD.


Assuntos
Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/terapia , Valva Aórtica/patologia , Aterosclerose/sangue , Aterosclerose/terapia , Calcinose/sangue , Calcinose/terapia , Lipoproteína(a)/sangue , Animais , Valva Aórtica/efeitos dos fármacos , Estenose da Valva Aórtica/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Calcinose/genética , Humanos , Lipoproteína(a)/genética , Terapia de Alvo Molecular
6.
Nat Rev Cardiol ; 16(5): 305-318, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30675027

RESUMO

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doença da Artéria Coronariana , Lipoproteína(a)/metabolismo , Fosfolipídeos/metabolismo , Calcificação Vascular/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Calcinose/metabolismo , Calcinose/prevenção & controle , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Descoberta de Drogas , Humanos , Oxirredução
7.
J Clin Lipidol ; 12(6): 1335-1345, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30527801

RESUMO

Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels.


Assuntos
Aterosclerose/metabolismo , Lipoproteína(a)/metabolismo , Aterosclerose/epidemiologia , Humanos , Lipoproteína(a)/química , Fatores de Risco
8.
J Clin Lipidol ; 12(6): 1358-1366, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30316749

RESUMO

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are an independent, and possibly causal, risk factor for atherothrombotic diseases including coronary heart disease. The principal evidence base for this comes from large population studies focusing on first atherothrombotic events. However, inconsistent findings have been reported from studies investigating the impact of elevated Lp(a) on atherothrombotic events in subjects with preexisting cardiovascular disease. This question is very important because the secondary prevention population is recommended for Lp(a) screening by some guidelines and could be an important target group for Lp(a)-lowering therapies that are currently on the horizon. In this review, we survey the secondary prevention literature as it relates to Lp(a) and identify some possible confounding factors that may underlie the inconsistent findings, such as index event bias.


Assuntos
Aterosclerose/complicações , Lipoproteína(a)/sangue , Prevenção Secundária/métodos , Trombose/sangue , Trombose/prevenção & controle , Humanos , Trombose/complicações
9.
Thromb Res ; 169: 1-7, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29990619

RESUMO

Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein which has been identified as a causal risk factor for coronary heart disease and calcific aortic valve disease. Lp(a) consists of a low-density lipoprotein (LDL) moiety covalently linked to the unique glycoprotein apolipoprotein(a) [apo(a)]. Apo(a) is homologous to the fibrinolytic zymogen plasminogen and thus may interfere with plasminogen activation. Conversion of native Glu-plasminogen by plasmin to the more readily activatable Lys-plasminogen greatly accelerates plasminogen activation and is necessary for optimal stimulation of plasminogen activation on endothelial cells. Lp(a)/apo(a) has been previously shown to inhibit pericellular plasminogen activation on vascular cells, but the mechanism underling these observations is unknown. We therefore explored whether apo(a) can inhibit pericellular Glu- to Lys-plasminogen conversion on cell surfaces. A physiologically relevant recombinant version of apo(a) (17K) significantly inhibits plasmin-mediated Glu- to Lys-plasminogen conversion on human umbilical vein endothelial cells (HUVECs) and smooth muscle cells (SMCs). All isoforms of apo(a) that were analyzed, ranging in size from 3 to 21 kringle IV type 2 repeats, were able to inhibit conversion to a similar extent. Removal of the kringle V and protease domain of apo(a) strongly reduces the ability of apo(a) to inhibit conversion on HUVECs and SMCs. Removing the strong lysine binding site in KIV10 of apo(a) abolishes its ability to inhibit conversion on HUVECs and, to a lesser extent, on SMCs. These results indicate a novel mechanism in which apo(a) inhibits the positive feedback mechanism that accelerates plasmin formation on vascular cells.


Assuntos
Apolipoproteínas A/metabolismo , Endotélio Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fragmentos de Peptídeos/metabolismo , Plasminogênio/metabolismo , Linhagem Celular , Fibrinolisina/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos
10.
Atherosclerosis ; 275: 11-21, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29852400

RESUMO

BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disorders including coronary heart disease and calcific aortic valve stenosis. Apolipoprotein(a) (apo(a)), the unique glycoprotein component of Lp(a), contains sequences homologous to plasminogen. Plasminogen activation is markedly accelerated in the presence of cell surface receptors and can be inhibited in this context by apo(a). METHODS: We evaluated the role of potential receptors in regulating plasminogen activation and the ability of apo(a) to mediate inhibition of plasminogen activation on vascular and monocytic/macrophage cells through knockdown (siRNA or blocking antibodies) or overexpression of various candidate receptors. Binding assays were conducted to determine apo(a) and plasminogen receptor interactions. RESULTS: The urokinase-type plasminogen activator receptor (uPAR) modulates plasminogen activation as well as plasminogen and apo(a) binding on human umbilical vein endothelial cells (HUVECs), human acute monocytic leukemia (THP-1) cells, and THP-1 macrophages as determined through uPAR knockdown and overexpression. Apo(a) variants lacking either the kringle V or the strong lysine binding site in kringle IV type 10 are not able to bind to uPAR to the same extent as wild-type apo(a). Plasminogen activation is also modulated, albeit to a lower extent, through the Mac-1 (αMß2) integrin on HUVECs and THP-1 monocytes. Integrin αVß3 can regulate plasminogen activation on THP-1 monocytes and to a lesser extent on HUVECs. CONCLUSIONS: These results indicate cell type-specific roles for uPAR, αMß2, and αVß3 in promoting plasminogen activation and mediate the inhibitory effects of apo(a) in this process.


Assuntos
Apoproteína(a)/metabolismo , Células Endoteliais da Veia Umbilical Humana/enzimologia , Integrina alfaVbeta3/metabolismo , Antígeno de Macrófago 1/metabolismo , Macrófagos/enzimologia , Monócitos/enzimologia , Plasminogênio/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Ativação Enzimática , Humanos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Transdução de Sinais , Células THP-1
11.
Curr Opin Lipidol ; 29(3): 259-267, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29528858

RESUMO

PURPOSE OF REVIEW: Evidence continues to mount for an important role for elevated plasma concentrations of lipoprotein(a) [Lp(a)] in mediating risk of atherothrombotic and calcific aortic valve diseases. However, there continues to be great uncertainty regarding some basic aspects of Lp(a) biology including its biosynthesis and catabolism, its mechanisms of action in health and disease, and the significance of its isoform size heterogeneity. Moreover, the precise utility of Lp(a) in the clinic remains undefined. RECENT FINDINGS: The contribution of elevated Lp(a) to cardiovascular risk continues to be more precisely defined by larger studies. In particular, the emerging role of Lp(a) as a potent risk factor for calcific aortic valve disease has received much scrutiny. Mechanistic studies have identified commonalities underlying the impact of Lp(a) on atherosclerosis and aortic valve disease, most notably related to Lp(a)-associated oxidized phospholipids. The mechanisms governing Lp(a) concentrations remain a source of considerable dispute. SUMMARY: This article highlights some key remaining challenges in understanding Lp(a) actions and clinical significance. Most important in this regard is demonstration of a beneficial effect of lowering Lp(a), a development that is on the horizon as effective Lp(a)-lowering therapies are being tested in the clinic.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Aterosclerose/metabolismo , Calcinose/metabolismo , Lipoproteína(a)/metabolismo , Trombose/metabolismo , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Aterosclerose/patologia , Calcinose/patologia , Humanos , Fatores de Risco , Trombose/patologia
13.
J Am Coll Cardiol ; 71(2): 177-192, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29325642

RESUMO

Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.


Assuntos
Estenose da Valva Aórtica , Doenças Cardiovasculares , Lipoproteína(a)/sangue , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/prevenção & controle , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Determinação de Necessidades de Cuidados de Saúde , Pesquisa , Fatores de Risco , Estados Unidos
14.
J Stroke Cerebrovasc Dis ; 27(3): 606-619, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29141778

RESUMO

BACKGROUND: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. METHODS: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. CONCLUSIONS: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.


Assuntos
Fibrilação Atrial , Isquemia Encefálica , Comunicação Interdisciplinar , Projetos de Pesquisa , Acidente Vascular Cerebral , Pesquisa Médica Translacional/métodos , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/fisiopatologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/fisiopatologia , Comportamento Cooperativo , Bases de Dados Factuais , Avaliação da Deficiência , Modelos Animais de Doenças , Eletrocardiografia Ambulatorial , Feminino , Humanos , Masculino , Ontário/epidemiologia , Prognóstico , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia
15.
Crit Rev Clin Lab Sci ; 55(1): 33-54, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29262744

RESUMO

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). Genetic, epidemiological and in vitro data provide strong evidence for a pathogenic role for Lp(a) in the progression of atherothrombotic disease. Despite these advancements and a race to develop new Lp(a) lowering therapies, there are still many unanswered and emerging questions about the metabolism and pathophysiology of Lp(a). New studies have drawn attention to Lp(a) as a contributor to novel pathogenic processes, yet the mechanisms underlying the contribution of Lp(a) to CVD remain enigmatic. New therapeutics show promise in lowering plasma Lp(a) levels, although the complete mechanisms of Lp(a) lowering are not fully understood. Specific agents targeted to apolipoprotein(a) (apo(a)), namely antisense oligonucleotide therapy, demonstrate potential to decrease Lp(a) to levels below the 30-50 mg/dL (75-150 nmol/L) CVD risk threshold. This therapeutic approach should aid in assessing the benefit of lowering Lp(a) in a clinical setting.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doença das Coronárias , Lipoproteína(a)/sangue , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/epidemiologia , Calcinose/sangue , Calcinose/tratamento farmacológico , Calcinose/epidemiologia , Fármacos Cardiovasculares/uso terapêutico , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/epidemiologia , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Fatores de Risco , Pesquisa Médica Translacional
16.
Prog Lipid Res ; 68: 57-82, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28888913

RESUMO

Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran).


Assuntos
Cardiologia/métodos , Lipoproteína(a) , Animais , Humanos , Hipolipemiantes/farmacologia , Lipoproteína(a)/química , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo
17.
JCI Insight ; 2(15)2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28768900

RESUMO

Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.

18.
Expert Rev Cardiovasc Ther ; 15(10): 797-807, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28816078

RESUMO

INTRODUCTION: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder. Gene variant in the LPA gene, which encodes for apolipoprotein(a), has been associated at the genome-wide level with CAVD. The process whereby Lp(a) promotes the development of CAVD is under intensive investigation and recent data have shed important insights into disease biology. In this regard, autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes the mineralization of the aortic valve. Areas covered: In this paper, we are reviewing the biology of Lp(a) and the latest discoveries about the molecular processes that link this lipoprotein with the development of CAVD including the role of ATX. Expert commentary: Elevated Lp(a) levels are genetically determined and considered as an important risk factor for CAVD. Understanding how Lp(a) promotes the development/progression of CAVD is crucial as it may hold promise for the development of new therapies.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Calcinose/fisiopatologia , Lipoproteína(a)/metabolismo , Humanos , Diester Fosfórico Hidrolases/metabolismo , Prevalência , Fatores de Risco
19.
PLoS One ; 12(7): e0180869, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28750079

RESUMO

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for cardiovascular disease. The mechanisms underlying Lp(a) clearance from plasma remain unclear, which is an obvious barrier to the development of therapies to specifically lower levels of this lipoprotein. Recently, it has been documented that monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) can lower plasma Lp(a) levels by 30%. Since PCSK9 acts primarily through the low density lipoprotein receptor (LDLR), this result is in conflict with the prevailing view that the LDLR does not participate in Lp(a) clearance. To support our recent findings in HepG2 cells that the LDLR can act as a bona fide receptor for Lp(a) whose effects are sensitive to PCSK9, we undertook a series of Lp(a) internalization experiments using different hepatic cells, with different variants of PCSK9, and with different members of the LDLR family. We found that PCSK9 decreased Lp(a) and/or apo(a) internalization by Huh7 human hepatoma cells and by primary mouse and human hepatocytes. Overexpression of human LDLR appeared to enhance apo(a)/Lp(a) internalization in both types of primary cells. Importantly, internalization of Lp(a) by LDLR-deficient mouse hepatocytes was not affected by PCSK9, but the effect of PCSK9 was restored upon overexpression of human LDLR. In HepG2 cells, Lp(a) internalization was decreased by gain-of-function mutants of PCSK9 more than by wild-type PCSK9, and a loss-of function variant had a reduced ability to influence Lp(a) internalization. Apo(a) internalization by HepG2 cells was not affected by apo(a) isoform size. Finally, we showed that very low density lipoprotein receptor (VLDLR), LDR-related protein (LRP)-8, and LRP-1 do not play a role in Lp(a) internalization or the effect of PCSK9 on Lp(a) internalization. Our findings are consistent with the idea that PCSK9 inhibits Lp(a) clearance through the LDLR, but do not exclude other effects of PCSK9 such as on Lp(a) biosynthesis.


Assuntos
Endocitose , Lipoproteína(a)/metabolismo , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Animais , Apolipoproteínas A/metabolismo , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mutação/genética , Isoformas de Proteínas/metabolismo
20.
Cardiovasc Res ; 113(11): 1351-1363, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472283

RESUMO

Aims: Oxidatively modified lipoproteins may promote the development/progression of calcific aortic valve stenosis (CAVS). Oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA), a lipid mediator that accumulates in mineralized aortic valves. LPA activates at least six different G protein-coupled receptors, which may play a role in the pathophysiology of CAVS. We hypothesized that LPA derived from OxLDL may promote a NF-κB signature that drives osteogenesis in the aortic valve. Methods and results: The role of OxLDL-LPA was examined in isolated valve interstitial cells (VICs) and the molecular pathway was validated in human explanted aortic valves and in a mouse model of CAVS. We found that OxLDL-LPA promoted the mineralization and osteogenic transition of VICs through LPAR1 and the activation of a RhoA-NF-κB pathway. Specifically, we identified that RhoA/ROCK activated IκB kinase alpha, which promoted the phosphorylation of p65 on serine 536 (p65 pS536). p65 pS536 was recruited to the BMP2 promoter and directed an osteogenic program not responsive to the control exerted by the inhibitor of kappa B. In LDLR-/-/ApoB100/100/IGFII transgenic mice (IGFII), which develop CAVS under a high-fat and high-sucrose diet the administration of Ki16425, a Lpar1 blocker, reduced by three-fold the progression rate of CAVS and also decreased the osteogenic activity as measured with a near-infrared fluorescent probe that recognizes hydroxyapatite of calcium. Conclusions: OxLDL-LPA promotes an osteogenic program in the aortic valve through a LPAR1-RhoA/ROCK-p65 pS536 pathway. LPAR1 may represent a suitable target to prevent the progression of CAVS.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/metabolismo , Lipoproteínas LDL/metabolismo , NF-kappa B/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Valva Aórtica/metabolismo , Humanos , Lisofosfolipídeos/farmacologia , Camundongos , Fosforilação , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo
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