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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 Neurointerv Surg ; 11(11): 1155-1161, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31088940

RESUMO

BACKGROUND: The efficacy of acute ischemic stroke treatment is affected by thrombus composition and age, yet no diagnostic method capable of quantitative thrombus characterization currently exists. This in vitro study evaluates the use of R2* , quantitative susceptibility mapping (QSM), and proton density fat fraction (FF) maps derived from a single gradient echo (GRE) MRI acquisition for characterizing clot of various hematocrit, as well as added calcified and lipidic components, throughout aging. METHODS: Two thrombus phantoms containing porcine clots (10-60% hematocrit, one with added calcium or lard) were scanned serially throughout 6 days of aging. Three-dimensional multi-echo GRE imaging was used to generate R2* , QSM, and FF maps, from which mean values for all clots at every time point were obtained. Receiver operating characteristic analysis was used to derive thresholds differentiating acute from chronic clot, and measured R2* and QSM were tested for their ability to estimate clot hematocrit. RESULTS: R2* and QSM varied minimally over the first 6 hours of aging (acute), and QSM was found to linearly relate to clot hematocrit. Beyond 6 hours (chronic), R2* and QSM increased considerably over time and hematocrit could be estimated from the R2* /QSM ratio. R2* and QSM thresholds of 22 s-1 and 0.165 ppm differentiated acute from chronic clots with a sensitivity/specificity of 100%/100% and 85%/92%, respectively. QSM and FF maps definitively distinguished calcium and lipid, respectively, from clots of any hematocrit and age. CONCLUSIONS: R2* , QSM, and FF from a single multi-echo GRE scan discriminated hematocrit and age, and distinguished calcification and lipid withinin vitro clot.


Assuntos
Senescência Celular , Eritrócitos/patologia , Interpretação de Imagem Assistida por Computador/métodos , Imagens de Fantasmas , Trombose/diagnóstico por imagem , Animais , Isquemia Encefálica/diagnóstico por imagem , Senescência Celular/fisiologia , Hematócrito/métodos , Imagem por Ressonância Magnética/métodos , Imagens de Fantasmas/tendências , Acidente Vascular Cerebral/diagnóstico por imagem , Suínos
4.
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
5.
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
6.
Circulation ; 139(12): 1472-1482, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30667276

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] levels predict the risk of myocardial infarction (MI) in populations of European ancestry; however, few data are available for other ethnic groups. Furthermore, differences in isoform size distribution and the associated Lp(a) concentrations have not fully been characterized between ethnic groups. METHODS: We studied 6086 cases of first MI and 6857 controls from the INTERHEART study that were stratified by ethnicity and adjusted for age and sex. A total of 775 Africans, 4443 Chinese, 1352 Arabs, 1856 Europeans, 1469 Latin Americans, 1829 South Asians, and 1221 Southeast Asians were included in the study. Lp(a) concentration was measured in each participant using an assay that was insensitive to isoform size, with isoform size being assessed by Western blot in a subset of 4219 participants. RESULTS: Variations in Lp(a) concentrations and isoform size distributions were observed between populations, with Africans having the highest Lp(a) concentration (median=27.2 mg/dL) and smallest isoform size (median=24 kringle IV repeats). Chinese samples had the lowest concentration (median=7.8 mg/dL) and largest isoform sizes (median=28). Overall, high Lp(a) concentrations (>50 mg/dL) were associated with an increased risk of MI (odds ratio, 1.48; 95% CI, 1.32-1.67; P<0.001). The association was independent of established MI risk factors, including diabetes mellitus, smoking, high blood pressure, and apolipoprotein B and A ratio. An inverse association was observed between isoform size and Lp(a) concentration, which was consistent across ethnic groups. Larger isoforms tended to be associated with a lower risk of MI, but this relationship was not present after adjustment for concentration. Consistent with variations in Lp(a) concentration across populations, the population-attributable risk of high Lp(a) for MI varied from 0% in Africans to 9.5% in South Asians. CONCLUSIONS: Lp(a) concentration and isoform size varied markedly between ethnic groups. Higher Lp(a) concentrations were associated with an increased risk of MI and carried an especially high population burden in South Asians and Latin Americans. Isoform size was inversely associated with Lp(a) concentration, but did not significantly contribute to risk.


Assuntos
Lipoproteína(a)/sangue , Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Apolipoproteínas A/análise , Apolipoproteínas B/análise , Pressão Sanguínea , Estudos de Casos e Controles , Complicações do Diabetes/diagnóstico , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etnologia , Razão de Chances , Isoformas de Proteínas/sangue , Fatores de Risco , Fumar
7.
Lancet ; 392(10155): 1281-1282, 2018 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-30293767
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
12.
Curr Probl Cancer ; 42(2): 215-230, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29459177

RESUMO

Pro-carboxypeptidase B2 (pro-CPB2) or thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein encoded by the CPB2 gene and deregulated in several cancer types, including breast cancer. Thrombin binding to thrombomodulin (TM), encoded by THBD, is important for TAFI activation. CPB2 gene expression is influenced by genetic polymorphism and cytokines such as interleukin 10 (IL-10). Our previous results showed that tumor infiltrating monocytes/macrophages (CD14+/CD16+) isolated from inflammatory breast cancer (IBC) patients' secrete high levels of IL-10. The aim of the present study is to test genetic polymorphism and expression of CPB2 in healthy breast tissues and carcinoma tissues of non-IBC and IBC patients. Furthermore, to investigate whether IL-10 modulates the expression of CPB2 and THBD in vivo and in-vitro. We tested CPB2 Thr325Ile polymorphism using restriction fragment length polymorphism, (RFLP) technique in healthy and carcinoma breast tissues. The mRNA expression of CPB2, THBD and IL10 were assessed by RT-qPCR. Infiltration of CD14+ cells was assessed by immunohistochemistry. In addition, we investigated the correlation between infiltration of CD14+ cells and expression of IL10 and CPB2. Furthermore, we correlated IL10 expression with the expression of both CPB2 and THBD in breast carcinoma tissues. Finally, we validated the role of recombinant IL-10 in regulating the expression of CPB2 and THBD using different breast cancer cell lines. Our results showed that CPB2 genotypes carrying the high-risk allele [Thr/Ile (CT) and Ile/Ile (TT)] were more frequent in both IBC and non-IBC patients compared to control group. CPB2 genotypes did not show any statistical correlation with CPB2 mRNA expression levels or patients' clinical pathological properties. Interestingly, CPB2 and IL10 expression were significantly higher and positively correlated with the incidence of CD14+ cells in carcinoma tissues of IBC as compared to non-IBC. On the other hand, THBD expression was significantly lower in IBC carcinoma versus non-IBC tissues. Based on molecular subtypes, CPB2 and IL10 expression were significantly higher in triple negative (TN) as compared to hormonal positive (HP) carcinoma tissues of IBC. Moreover, CPB2 expression was positively correlated with presence of lymphovascular invasion and the expression of IL10 in carcinoma tissues of IBC patients. Furthermore, recombinant human IL-10 stimulated CPB2 expression in SUM-149 (IBC cell line) but not in MDA-MB-231 (non-IBC cell line), while there was no significant effect THBD expression. In conclusion, carcinoma tissues of IBC patients are characterized by higher expression of CPB2 and lower expression of THBD. Moreover, CPB2 positively correlates with IL10 mRNA expression, incidence of CD14+ cells and lymphovascular invasion in IBC patients. IL-10 stimulated CPB2 expression in TN-IBC cell line suggests a relevant role of CPB2 in the aggressive phenotype of IBC.


Assuntos
Carboxipeptidase B2/genética , Neoplasias Inflamatórias Mamárias/sangue , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/patologia , Interleucina-10/sangue , Macrófagos/patologia , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Inflamatórias Mamárias/imunologia , Interleucina-10/genética , Interleucina-10/farmacologia , Metástase Linfática , Macrófagos/fisiologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Vasculares/secundário
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.
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
18.
Clin Exp Metastasis ; 34(2): 155-169, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28124276

RESUMO

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen present in blood plasma. Proteolytic activation of TAFI by thrombin, thrombin in complex with the endothelial cell cofactor thrombomodulin, or plasmin results in an enzyme (TAFIa) that removes carboxyl-terminal lysine residues from protein and peptide substrates, including cell-surface plasminogen receptors. TAFIa is therefore capable of inhibiting plasminogen activation in the pericellular milieu. Since plasminogen activation has been linked to angiogenesis, TAFIa could therefore have anti-angiogenic properties, and indeed TAFIa has been shown to inhibit endothelial tube formation in a fibrin matrix. In this study, the TAFI pathway was manipulated by providing exogenous TAFI or TAFIa or by adding a potent and specific inhibitor of TAFIa. We found that TAFIa elicited a series of anti-angiogenic responses by endothelial cells, including decreased endothelial cell proliferation, cell invasion, cell migration, tube formation, and collagen degradation. Moreover, TAFIa decreased tube formation and proteolysis in endothelial cell culture grown alone and in co-culture with breast cancer cell lines. In accordance with these findings, inhibition of TAFIa increased secretion of matrix metalloprotease proenzymes by endothelial and breast cancer cells. Finally, treatment of endothelial cells with TAFIa significantly inhibited plasminogen activation. Taken together our results suggest a novel role for TAFI in inhibiting tumour angiogenic behaviors in breast cancer.


Assuntos
Neoplasias da Mama/patologia , Carboxipeptidase B2/fisiologia , Células Endoteliais/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Carboxipeptidase B2/antagonistas & inibidores , Carboxipeptidase B2/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Colágeno Tipo IV/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Precursores Enzimáticos/farmacologia , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Plasminogênio/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia
19.
Curr Atheroscler Rep ; 18(12): 69, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27761705

RESUMO

PURPOSE OF REVIEW: Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for cardiovascular diseases including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis. This review summarizes the rationale for Lp(a) lowering and surveys relevant clinical trial data using a variety of agents capable of lowering Lp(a). RECENT FINDINGS: Contemporary guidelines and recommendations outline populations of patients who should be screened for elevated Lp(a) and who might benefit from Lp(a) lowering. Therapies including drugs and apheresis have been described that lower Lp(a) levels modestly (∼20 %) to dramatically (∼80 %). Existing therapies that lower Lp(a) also have beneficial effects on other aspects of the lipid profile, with the exception of Lp(a)-specific apheresis and an antisense oligonucleotide that targets the mRNA encoding apolipoprotein(a). No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering confers a benefit in terms of ameliorating cardiovascular risk, although additional outcome trials of therapies that lower Lp(a) are ongoing. It is more likely, however, that Lp(a)-specific agents will provide the most appropriate approach for addressing this question.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Lipoproteína(a)/metabolismo , Animais , Remoção de Componentes Sanguíneos , Humanos , Lipoproteína(a)/genética , Oligonucleotídeos Antissenso/uso terapêutico , Fatores de Risco
20.
BMC Cancer ; 16: 328, 2016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27221823

RESUMO

BACKGROUND: Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen, which can be converted to activated TAFI (TAFIa) through proteolytic cleavage by thrombin, plasmin, and most effectively thrombin in complex with the endothelial cofactor thrombomodulin (TM). TAFIa is a carboxypeptidase that cleaves carboxyl terminal lysine and arginine residues from protein and peptide substrates, including plasminogen-binding sites on cell surface receptors. Carboxyl terminal lysine residues play a pivotal role in enhancing cell surface plasminogen activation to plasmin. Plasmin has many critical functions including cleaving components of the extracellular matrix (ECM), which enhances invasion and migration of cancer cells. We therefore hypothesized that TAFIa could act to attenuate metastasis. METHODS: To assess the role of TAFIa in breast cancer metastasis, in vitro migration and invasion assays, live cell proteolysis and cell proliferation using MDA-MB-231 and SUM149 cells were carried out in the presence of a TAFIa inhibitor, recombinant TAFI variants, or soluble TM. RESULTS: Inhibition of TAFIa with potato tuber carboxypeptidase inhibitor increased cell invasion, migration and proteolysis of both cell lines, whereas addition of TM resulted in a decrease in all these parameters. A stable variant of TAFIa, TAFIa-CIIYQ, showed enhanced inhibitory effects on cell invasion, migration and proteolysis. Furthermore, pericellular plasminogen activation was significantly decreased on the surface of MDA-MB-231 and SUM149 cells following treatment with various concentrations of TAFIa. CONCLUSIONS: Taken together, these results indicate a vital role for TAFIa in regulating pericellular plasminogen activation and ultimately ECM proteolysis in the breast cancer microenvironment. Enhancement of TAFI activation in this microenvironment may be a therapeutic strategy to inhibit invasion and prevent metastasis of breast cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carboxipeptidase B2/farmacologia , Movimento Celular , Plasminogênio/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteólise , Trombomodulina/metabolismo , Células Tumorais Cultivadas
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