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1.
Circulation ; 128(22): 2351-63, 2013 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-24043300

RESUMO

BACKGROUND: Smooth muscle cell (SMC) migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan-deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMCs and tested for podocan expression in human atherosclerosis. In all these conditions, we concomitantly evaluated the Wnt-TCF (T-cell factor) pathway. METHODS AND RESULTS: Podocan was strongly and selectively expressed in arteries of wild-type mice after injury. Podocan-deficient mice showed increased arterial lesion formation compared with wild-type littermates in response to injury (P<0.05). Also, SMC proliferation was increased in arteries of podocan-deficient mice compared with wild-type (P<0.05). In vitro, migration and proliferation were increased in podocan-deficient SMCs and were normalized by transfection with the wild-type podocan gene (P<0.05). In addition, upregulation of the Wnt-TCF pathway was found in SMCs of podocan-deficient mice both in vitro and in vivo. On the other hand, podocan overexpression in human SMCs significantly reduced SMC migration and proliferation, inhibiting the Wnt-TCF pathway. Podocan and a Wnt-TCF pathway marker were differently expressed in human coronary restenotic versus primary lesions. CONCLUSIONS: Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMCs. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF pathway.


Assuntos
Movimento Celular/fisiologia , Glicoproteínas/genética , Músculo Liso Vascular/patologia , Neointima/patologia , Neointima/fisiopatologia , Placa Aterosclerótica/patologia , Adulto , Idoso , Animais , Aorta/patologia , Aorta/fisiologia , Proliferação de Células , Células Cultivadas , Feminino , Artéria Femoral/lesões , Artéria Femoral/patologia , Artéria Femoral/fisiologia , Expressão Gênica/fisiologia , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/fisiologia , Placa Aterosclerótica/fisiopatologia , Transfecção , Via de Sinalização Wnt/fisiologia
2.
Cardiol J ; 20(3): 268-76, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23788301

RESUMO

BACKGROUND: The pathomechanisms underlying aortic valve degeneration are incompletely understood. Therefore, the aim of our work was to assess the quantitative changes of proliferation and apoptosis accompanied by cellular phenotype alternations and matrix secretionin aortic sclerotic and stenotic valves and degenerative bioprostheses, as well as to detect the expression pattern of the rapamycin receptor FKBP12 across these three valve types. METHODS: Mild-to-moderate sclerotic and stenotic valves and degenerative bioprostheses from 30 patients (n = 10 per group) were collected at autopsy or by surgery. Ki67+, FKBP12+, alpha-actin+, HSP47+ and TUNEL+ apoptotic cells were analyzed by immunohistochemistry. RESULTS: The main finding was the reduced proliferation and increased apoptosis in stenotic valves (ST) compared to the sclerotic ones (SC) (proliferation: ST: 20.8 ± 2.0% vs. SC: 30.1 ±2.2%, apoptosis: ST: 40.7 ± 5.0% vs. SC: 28.0 ± 5.1%, p < 0.05, respectively). Analogical alternations were found in degenerative bioprostheses (BP) (proliferation: 4.8 ± 2.3%; apoptosis: 13.1 ± 6.8%). Corresponding changes were observed in the valve cellularity (ST: 893 ± 168, SC: 1034 ± 284, BP: 385 ± 179 cells/mm2, p < 0.05, respectively). The FKBP12 signaling was reduced in diseased valves and bioprostheses (ST: 28.1 ± 3.6%, SC: 42.2 ± 3.8%, BP: 5.8 ± 1.9%, p < 0.05, respectively). Further, the augmented alpha-actin expressionwas observed as the degenerative process progressed (ST: 30.3 ± 5.0%, SC: 22.6 ± 2.7%, BP:8.7 ± 4.0%, p < 0.05, respectively), followed by the upregulation of HSP47 (ST: 22.6 ± 2.8%,SC: 15.4 ± 2.1%, BP: 3.4 ± 1.0%, p < 0.05, respectively) and consecutive matrix accumulation. CONCLUSIONS: The imbalance between proliferation and apoptosis with cellular phenotypical shift and subsequent matrix secretion may contribute to aortic valve stenosis and bioprosthesis degeneration. The identification of FKBP12 expression may implicate potential therapeutic strategies.


Assuntos
Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/cirurgia , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Apoptose , Bioprótese , Proliferação de Células , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Falha de Prótese , Actinas/análise , Idoso , Valva Aórtica/química , Estenose da Valva Aórtica/metabolismo , Autopsia , Biomarcadores/análise , Feminino , Fibrose , Proteínas de Choque Térmico HSP47/análise , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Desenho de Prótese , Índice de Gravidade de Doença , Proteína 1A de Ligação a Tacrolimo/análise , Resultado do Tratamento
3.
Arterioscler Thromb Vasc Biol ; 33(5): 1036-45, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23430616

RESUMO

OBJECTIVE: Atherosclerosis and restenosis are multifactorial diseases associated with abnormal vascular smooth muscle cell (VSMC) proliferation. Nuclear factor-Y (NF-Y) plays a major role in transcriptional activation of the CYCLIN B1 gene (CCNB1), a key positive regulator of cell proliferation and neointimal thickening. Here, we investigated the role of NF-Y in occlusive vascular disease. APPROACH AND RESULTS: We performed molecular and expression studies in cultured cells, animal models, and human tissues. We find upregulation of NF-Y and cyclin B1 expression in proliferative regions of murine atherosclerotic plaques and mechanically induced lesions, which correlates with higher binding of NF-Y to target sequences in the CCNB1 promoter. NF-YA expression in neointimal lesions is detected in VSMCs, macrophages, and endothelial cells. Platelet-derived growth factor-BB, a main inductor of VSMC growth and neointima development, induces the recruitment of NF-Y to the CCNB1 promoter and augments both CCNB1 mRNA expression and cell proliferation through extracellular signal-regulated kinase 1/2 and Akt activation in rat and human VSMCs. Moreover, adenovirus-mediated overexpression of a NF-YA-dominant negative mutant inhibits platelet-derived growth factor-BB-induced CCNB1 expression and VSMC proliferation in vitro and neointimal lesion formation in a mouse model of femoral artery injury. We also detect NF-Y expression and DNA-binding activity in human neointimal lesions. CONCLUSIONS: Our results identify NF-Y as a key downstream effector of the platelet-derived growth factor-BB-dependent mitogenic pathway that is activated in experimental and human vasculoproliferative diseases. They also identify NF-Y inhibition as a novel and attractive strategy for the local treatment of neointimal formation induced by vessel denudation.


Assuntos
Fator de Ligação a CCAAT/fisiologia , Músculo Liso Vascular/citologia , Neointima/etiologia , Animais , Apolipoproteínas E/fisiologia , Aterosclerose/etiologia , Becaplermina , Fator de Ligação a CCAAT/antagonistas & inibidores , Proliferação de Células , Células Cultivadas , Ciclina B1/genética , Células Endoteliais/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neointima/terapia , Proteínas Proto-Oncogênicas c-sis/farmacologia , Ratos , Ratos Wistar
4.
Basic Res Cardiol ; 106(4): 657-65, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21416407

RESUMO

Heat shock proteins (HSPs) are among the most highly conserved and immunogenic proteins shared by microbial agents and mammals. Human (h) HSP60 is upregulated under stress conditions and serves as a target for cross-reactive cytotoxic HSP-serum-antibodies. The present study evaluates the expressions of hHSP60 and its homologue chlamydial (c) HSP60 in advanced human coronary lesions and correlates intimal tissue-bound HSP expressions with circulating HSP-antibodies. Coronary atherectomy specimens retrieved from 100 primary target lesions of patients with unstable angina (UA; n = 40) or stable angina (SA; n = 60) were assessed immunohistochemically for the presence of hHSP60 and cHSP60. In a subgroup (n = 40), blood samples were tested for anti-Chl. pn.-IgG/IgA-titers and anti-HSP65-antibody titers. Coronary plaques revealed immunoreactive hHSP60 in 55% and cHSP60 in 45% of the lesions. Expression of both HSP homologues was significantly (each p < 0.001) higher in UA lesions compared with SA lesions (7.4 vs. 1.2% and 6.0 vs. 1.1%). HSP homologues showed positive correlations both in UA- and SA-lesions (r = 0.41, 0.33; p < 0.05). cHSP60 showed no association with anti-Chl. pn.-IgG/IgA-titers, whereas expressions of both homologues correlated positive with anti-HSP65-Ab titers (r = 0.42, p < 0.05; r = 0.50, p < 0.01). Intimal amounts of HSP60 homologues were associated with increased expressions of C-reactive protein, Toll-like receptor-4 and tissue factor. Human and chlamydial HSP60 colocalize within coronary atheroma, most prevalent in lesions associated with UA. Our data demonstrate a significant correlation between the intimal expressions of HSP60 homologues and serum HSP65 antibodies, thereby suggesting that humoral immune reactions may play an important role in coronary atherosclerosis and plaque instability.


Assuntos
Angina Instável/metabolismo , Anticorpos/sangue , Chaperonina 60/análise , Proteínas de Choque Térmico/imunologia , Idoso , Proteína C-Reativa/análise , Doença da Artéria Coronariana/etiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tromboplastina/análise , Receptor 4 Toll-Like/análise
5.
FASEB J ; 25(1): 35-44, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20813982

RESUMO

The complement component C5a is formed during activation of the complement cascade and exerts chemotactic and proinflammatory effects. Macrophages, which are localized in the rupture-prone shoulder regions of coronary plaques, are thought to play a major role in plaque destabilization and rupture through the production of matrix metalloproteinases (MMPs). When human monocyte-derived macrophages were stimulated in vitro with C5a, MMP-1 and MMP-9 mRNA levels were significantly increased. Furthermore, C5a up-regulated MMP-1 and MMP-9 antigens and activity, as determined by ELISA and specific activity assays. These effects were blocked by antibodies against the receptor C5aR/CD88. In addition, blocking experiments revealed that MMP-1 expression was mediated by activation of the transcription factor AP-1, and MMP-9 expression was induced by activation of NF-κB and AP-1. Immunohistochemical analysis of human coronary plaques demonstrated the colocalization of C5a, MMP-1, and MMP-9 in vivo. Together, these observations indicate that activation of the complement cascade and formation of C5a may play a role in the onset of acute coronary events by induction of MMPs in atherosclerotic lesions.


Assuntos
Complemento C5a/metabolismo , Vasos Coronários/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Células Cultivadas , Complemento C5a/genética , Complemento C5a/farmacologia , Vasos Coronários/patologia , Imunofluorescência , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Masoprocol/farmacologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Placa Aterosclerótica/patologia , Quinazolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo
6.
EPMA J ; 2(1): 91-105, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23199131

RESUMO

Aortic stenosis (AS) is the most frequent valvular heart disease. Severe AS results in concentric left ventricular hypertrophy, and ultimately, the heart dilates and fails. During a long period of time patients remain asymptomatic. In this period a pathology progression should be monitored and effectively thwarted by targeted measures. A cascade of cellular and molecular events leads to chronic degeneration of aortic valves. There are some molecular attributes characteristic for the process of valvular degeneration with clear functional link between shifted cell-cycle control, calcification and tissue remodelling of aortic valves. Bioactivity of implanted bioprosthesis is assumed to result in its dysfunction. Age, gender (females), smoking, Diabetes mellitus, and high cholesterol level dramatically shorten the re-operation time. Therefore, predictive and preventive measures would be highly beneficial, in particular for young female diabetes-predisposed patients. Molecular signature of valvular degeneration is reviewed here with emphases on clinical meaning, risk-assessment, predictive diagnosis, individualised treatments.

7.
Thromb Res ; 126(2): e83-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20553948

RESUMO

INTRODUCTION: Depressive disorders have been identified as independent risk factors for coronary heart disease. The present study (i) compared platelet function of depressed patients with that of healthy controls, (ii) analysed possible aggregability changes during 3 months of treatment with antidepressants, and (iii) sought to assess different effects of escitalopram and nortriptyline on platelet aggregation. METHODS: Blood samples of 91 major depressed patients and 91 healthy controls were analysed with whole blood aggregometry in a case-control setting. Depressed patients were randomized to two groups treated either with escitalopram (n=47) or nortriptyline (n=44). Platelet aggregation was studied on days 0, 1, 3, 7, 14, 21, 84 of continuing medication and was determined in response to adenosine diphosphate (ADP) and collagen. RESULTS: Platelet aggregation induced by ADP was increased among depressive patients compared with that of healthy controls (26%, p=0.006). With antidepressant treatment, changes in platelet aggregation remained comparable in both groups at early time points (d1 to 21). In contrast, at day 84, patients with antidepressive response revealed significant differences in both medication groups: Patients receiving escitalopram showed a 23% decrease of ADP induced aggregation (p=0.03) and a 15% decrease of collagen induced aggregation (p=0.03). With nortriptyline the increase in impedance was reduced by 29% after ADP induction (p=0.046). CONCLUSION: Depressed patients have higher ex vivo platelet aggregation that may contribute to increased cardiovascular morbidity. After three months of antidepressant treatment with either escitalopram or nortriptyline, platelet aggregation was significantly reduced in antidepressant responders, irrespective of the antidepressant medication type.


Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Nortriptilina/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Adulto , Plaquetas/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Cardiovasc Pathol ; 19(6): e205-10, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19914090

RESUMO

BACKGROUND: Increasing evidence supports a link between serological evidence of pathogen burden (PB) and the risk for future cardiovascular events. Our study evaluates the intimal presence of 4 pathogens in atheroma, clinically associated with acute coronary syndromes (ACS) and stable angina (SA), and the effect on the expression of intimal C-reactive protein (CRP), tissue factor (TF) and human heat-shock protein 60 (hHSP60). METHODS: Coronary atherectomy specimens retrieved from 60 primary lesions of patients with ACS (n=35) or SA (n=25) were assessed immunohistochemically for the presence of Chlamydia pneumoniae (Cpn), Helicobacter pylori (HP), Cytomegalovirus (CMV) and Epstein­Barr Virus (EBV) and for the expression of CRP, TF, and hHSP60. RESULTS: Analysis revealed eight lesions without, 22 lesions with one, 19 lesions with two, seven lesions with three, and four lesions with four pathogens. Cpn was present in 73%, HP in 31%, CMV in 16%, and EBV in 40%. Mean value of PB in ACS-lesions was significantly increased. Expressions of CRP, TF, and hHSP60 were significantly higher in ACS lesions. The number of infectious pathogens correlated significant with the expressions of CRP, TF, and hHSP60. CONCLUSIONS: Our data demonstrate the impact of PB in plaque instability and suggest local proinflammatory, prothrombotic, and proimmunogenic effects.


Assuntos
Síndrome Coronariana Aguda , Angina Pectoris , Autoimunidade , Chlamydophila pneumoniae/patogenicidade , Citomegalovirus/patogenicidade , Helicobacter pylori/patogenicidade , Herpesvirus Humano 4/patogenicidade , Inflamação , Trombose , Síndrome Coronariana Aguda/imunologia , Síndrome Coronariana Aguda/microbiologia , Síndrome Coronariana Aguda/cirurgia , Síndrome Coronariana Aguda/virologia , Idoso , Angina Pectoris/imunologia , Angina Pectoris/microbiologia , Angina Pectoris/cirurgia , Angina Pectoris/virologia , Aterectomia Coronária , Proteína C-Reativa/análise , Chaperonina 60/análise , Distribuição de Qui-Quadrado , Vasos Coronários/imunologia , Vasos Coronários/microbiologia , Vasos Coronários/virologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , Tromboplastina/análise , Trombose/imunologia , Trombose/microbiologia , Trombose/virologia
9.
Cardiovasc Pathol ; 19(6): 353-60, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19747851

RESUMO

BACKGROUND: Increased proliferation, mitigated apoptosis, and recruitment of primarily extravascular cells to injured vessels are important processes during neointima formation. Therefore, the goal of this study was to assess the spatiotemporal balance between proliferation and apoptosis and the influence of apoptosis on the survival of primarily extravascular cells in in-stent neointima. METHODS: Minipigs underwent stent implantation to abdominal aortic segments. At Days 1, 7, 14, 30, 60, and 90 after injury, arterial cross sections were analyzed by TUNEL assay to detect apoptotic cells. For immunohistochemical detection of Ki67+/proliferating cell nuclear antigen (PCNA)+ proliferative, caspase3+ apoptotic, S100+/fascin+ dendritic, GFAP+ neural crest-derived cells and CD14+ monocytes/macrophages, the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method was used. RESULTS: In the incipient cell-rich neointima, both frequency of proliferation and apoptosis was maximal (Ki67, 28.5±2.2%; PCNA, 25.4±3.8%; TUNEL, 8.6±0.4%; caspase3, 7.9±4.3%). With time, parallel to the decline in the neointima cellularity, signaling for proliferation and apoptosis decreased. Throughout the time course of neointima development, the apoptotic activity was detected in primarily extravascular cells. CONCLUSIONS: Imbalance between proliferation and apoptosis and recruitment of dendritic cells, monocytes/macrophages, and neural crest-derived cells to the injured vessels may partly explain the formation of the hypercellular in-stent neointima. Herein, apoptosis is an important factor that regulates survival of primarily extravascular neointimal cells.


Assuntos
Angioplastia com Balão/instrumentação , Aorta Abdominal/patologia , Apoptose , Proliferação de Células , Stents , Túnica Íntima/patologia , Animais , Aorta Abdominal/metabolismo , Biomarcadores/metabolismo , Sobrevivência Celular , Hiperplasia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Suínos , Porco Miniatura , Fatores de Tempo , Túnica Íntima/metabolismo
10.
J Heart Valve Dis ; 18(4): 411-7, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19852145

RESUMO

BACKGROUND AND AIM OF THE STUDY: The presence of five pathogens was assessed, together with a possible correlation of the total pathogen burden on inflammation and (auto)immunity in aortic stenosis (AS) and degenerative aortic valve bioprosthesis (BP). METHODS: Diseased valve specimens from a total of 68 patients (52 with AS, 16 with BP) were studied. The presence and localization was assessed of Chlamydia pneumoniae (cHSP60), Helicobacter pylori (HP), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and herpes simplex virus (HSV), as well as of macrophages (CD68), C-reactive protein (CRP) and human heat shock protein 60 (hHSP60), by using immunohistochemical and morphometric analyses. RESULTS: In the majority of degenerative aortic valves, specific pathogens, inflammation and immunity were localized predominantly in the fibrosa of AS patients, and in superficial regions of the BP. The categorization of valves as having four or more pathogens (n = 37) or fewer pathogens (n = 31) demonstrated an increased signaling of CD68 (p = 0.03) and CRP (p = 0.02). Specifically, cHSP60, HP and hHSP60 levels were increased in valves where one or two bacteria were identified (n = 59) compared to those without bacterial presence (n = 9) (p = 0.04). CONCLUSION: The pathogen burden may contribute to valvular degeneration by promoting further deleterious inflammatory and (auto)immune processes at the level of the valvular fibrosa.


Assuntos
Estenose da Valva Aórtica/imunologia , Estenose da Valva Aórtica/microbiologia , Valva Aórtica/imunologia , Valva Aórtica/microbiologia , Bioprótese/microbiologia , Próteses Valvulares Cardíacas/microbiologia , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Proteína C-Reativa/metabolismo , Chaperonina 60/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade
13.
Atherosclerosis ; 202(1): 135-43, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18508060

RESUMO

BACKGROUND: Serum C-reactive protein (CRP) is a strong risk predictor of cardiovascular events, and tissue factor (TF) plays a central role in thrombus formation of advanced atherosclerotic plaques. Aim of the present study was to quantify in situ CRP and TF in coronary atherectomy specimens associated with acute coronary syndromes (ACS) or stable angina (SA). In addition, the effect of statin treatment on both intimal determinants was analyzed. METHODS AND RESULTS: Serial sections from atherectomy probes retrieved from coronary primary target lesions of 42 ACS and 70 SA patients were examined for CRP and TF expression using immunostaining. CRP and TF intimal expression was consistently higher in ACS lesions and a positive correlation between both determinants was detected. In both subgroups intimal staining intensity of CRP but not TF was strongly associated with serum CRP levels. Using angioscopy, complex plaques revealed a higher intimal CRP and TF expression than white/yellow plaques. Both CRP and TF were consistently lower expressed in target lesions of patients with pre-existing statin treatment. CONCLUSIONS: CRP and TF expression is markedly increased in plaques derived from patients with ACS as compared to SA patients. Statin treatment appears to reduce vascular expression of CRP and TF.


Assuntos
Síndrome Coronariana Aguda/metabolismo , Proteína C-Reativa/biossíntese , Regulação da Expressão Gênica , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Tromboplastina/biossíntese , Idoso , Angina Pectoris/metabolismo , Angina Pectoris/patologia , Angioscopia , Aterectomia Coronária , Aterosclerose/metabolismo , Aterosclerose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/metabolismo
14.
Infect Disord Drug Targets ; 8(2): 88-99, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18537704

RESUMO

Degenerative aortic valve stenosis is the leading cause of heart valve disease in elderly resulting in significant morbidity and mortality. Although aortic stenosis has been recognized as a complex inflammatory and well-regulated process, its exact pathomechanisms are still largely unknown. Assessment by Echocardiography, Electron Beam Computed Tomography and Multislice Computed Tomography is useful for monitoring of disease progression. However, better knowledge of main determinants is essential to enable both prediction and prevention of the disease. It has been suggested that the process of heart valve degeneration is associated with the risk factors of atherosclerosis and shares many histological and molecular characteristics. Morphologic, cellular and sub-cellular examinations of degenerative aortic valves revealed endothelial derangement, inflammatory infiltrates of macrophages, T-lymphocytes and foam cells, non-physiologic lipid/lipoprotein/protein deposits, as well as dramatically altered extra-cellular matrix composition and expression profiles of checkpoint- and "tissue remodeling"-genes. Metabolic disorder--Diabetes mellitus--is considered to predispose to degenerative valve disease and is associated with faster degeneration of bioprosthetic valves. Oxidative stress is implicated in progressive chronic degenerative processes secondary to diabetes. Moreover, diabetic patients are a high-risk group for infectious disorders. Increased prevalence of infectious endocarditis in patients with type 2 Diabetes mellitus contributes considerably to both acute aortic insufficiency and chronic progressive degeneration of valvular tissue. Cholesterol lowering drugs were demonstrated to be able to retard this progression. This review considers prognostic factors for prediction of progressive degenerative processes and novel targets to prevent calcification of aortic valves.


Assuntos
Estenose da Valva Aórtica/etiologia , Valva Aórtica/patologia , Complicações do Diabetes/epidemiologia , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico , Bioprótese/efeitos adversos , Cardiomiopatias/complicações , Cardiomiopatias/etiologia , Próteses Valvulares Cardíacas/efeitos adversos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
15.
J Heart Valve Dis ; 17(2): 187-93, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18512489

RESUMO

BACKGROUND AND AIM OF THE STUDY: Although degenerative calcific aortic valve stenosis is the most common valvular disease among the elderly, neither the etiology underlying the condition nor degeneration of the bioprostheses is yet fully understood. The study aim was to assess the expression profile of those OPG/RANKL/RANK-system determinants known to act as key regulators of bone metabolism and the immune system in calcific aortic valve stenosis and porcine aortic bioprostheses. METHODS: Valve probes from a total of 69 patients (41 with end-stage aortic stenosis, 11 with mild-to-moderate aortic sclerosis, 17 with degenerative porcine aortic bioprostheses) were explanted either during surgery or at autopsy. The presence and localization of OPG, RANKL, RANK and NF-kappaB were analyzed by immunostaining and morphometry. RESULTS: The majority of stenotic and sclerotic valves exhibited cell-bound signals of OPG, RANKL, RANK and NF-kappaB, while bioprostheses showed only sparse signaling. As key findings, the percentage of cells labeled by OPG, RANK and NF-kappaB was increased in sclerotic valves compared with stenotic valves (each p < 0.001), whereas the frequency of RANKL was higher in stenotic compared to sclerotic valves (p < 0.001). As a consequence, the OPG/RANKL ratio was decreased in stenotic (0.83) compared to sclerotic valves (20.2). CONCLUSION: The differential expression profile of specific members of the OPG/RANKL/RANK axis suggests an involvement of their determinants in native valve calcification, but not in the degeneration of porcine bioprostheses. Thus, these mediators of bone homeostasis may represent new targets for a more specified prevention and/or therapy of native aortic stenosis.


Assuntos
Estenose da Valva Aórtica/metabolismo , Próteses Valvulares Cardíacas , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Idoso , Estenose da Valva Aórtica/patologia , Bioprótese , Calcinose/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Estudos Retrospectivos
16.
J Vasc Res ; 45(2): 173-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17962721

RESUMO

Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 +/- 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 +/- 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2-12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 +/- 1.0%) that significantly differed from that found in primary stable atheroma (1.3 +/- 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Lesões das Artérias Carótidas/metabolismo , Reestenose Coronária/metabolismo , Estenose Coronária/metabolismo , Stents Farmacológicos , Sirolimo/administração & dosagem , Proteína 1A de Ligação a Tacrolimo/metabolismo , Túnica Íntima/metabolismo , Idoso , Animais , Aterectomia Coronária , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Cateterismo/efeitos adversos , Reestenose Coronária/patologia , Reestenose Coronária/terapia , Estenose Coronária/patologia , Estenose Coronária/terapia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia
17.
Cardiology ; 110(3): 199-205, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18057885

RESUMO

OBJECTIVES: In-stent restenosis due to neointima formation is a major limitation following stent implantation. Recently, several studies reported mobilization of primarily extravascular cells to the arterial sites after balloon angioplasty. Therefore, the goal of the present study was to assess the coordinated neointimal expression of endothelial progenitor, dendritic and neural crest-derived cells after stent implantation. METHODS: Male minipigs underwent stent implantation in abdominal aortic segments. Animals were sacrificed at 1, 7, 14, 30, 60 or 90 days. Cross sections of the injured vessels were obtained for immunohistochemistry using specific antibodies for the detection of endothelial progenitor (CD133), dendritic (S100) and neural crest-derived cells (GFAP), as well as monocytes/macrophages (CD14) and T lymphocytes (CD3). RESULTS: As a key finding, frequency of CD133, S100, GFAP, CD14 and CD3 (18.5 +/- 3.6, 14.9 +/- 1.8, 10.6 +/- 1.1, 40.2 +/- 8.3 and 5.0 +/- 0.6%, respectively) in neointima was maximal at day 7. With ongoing neointima enlargement, expression of these cells decreased. In advanced neointima, labeled cells were predominantly localized at luminal and stented sites. Media showed almost no immunoreactivity of the markers studied, whereas adventitial zones of neovascularization revealed some signals. CONCLUSIONS: Endothelial progenitor, dendritic, neural crest-derived and inflammatory cells are consistently recruited into arterial neointima, mostly at early time points after stent implantation.


Assuntos
Células Dendríticas/patologia , Células Endoteliais/patologia , Células-Tronco/patologia , Stents , Túnica Íntima/patologia , Antígeno AC133 , Animais , Antígenos CD/análise , Aorta Abdominal , Complexo CD3/análise , Células Dendríticas/classificação , Células Endoteliais/classificação , Proteína Glial Fibrilar Ácida/análise , Glicoproteínas/análise , Imuno-Histoquímica , Receptores de Lipopolissacarídeos/análise , Masculino , Peptídeos/análise , Proteínas S100/análise , Células-Tronco/classificação , Suínos , Porco Miniatura , Túnica Íntima/fisiopatologia
19.
Atherosclerosis ; 192(1): 75-84, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-16926016

RESUMO

Inflammation plays a central role in vascular repair, and spreads into perivascular tissue (PVT) following angioplasty. Chemokines (CK) and chemokine receptors (CKR) are key determinants of inflammatory chemotaxis. We sought to assess the arterial and perivascular expression of the CK CCL2 and CXCL2, and the CKR CCR2, CCR5, and CXCR4 in balloon-injured porcine coronary arteries. Vascular cells that express specific CK and CKR mRNA during post-angioplasty time course were detected by in situ hybridization (ISH), and expression was quantified by real time RT-PCR in PVT. CCL2 was maximal in PVT from 2 to 24h post injury, coincident with local macrophage-activation. Expression was upregulated in media and adventitia from 24h to 3 days, and in neointima at 7 days. CXCL2 was detected in media at 2 and 4h, and also in some neointimal cells. CCR2 and CCR5 were maximal in PVT at 24h and 3 days, respectively. Expression shifted to media and adventitia at 2 and 3 days, and to neointima and adventitia at 7 days, and was low at 14 days. CXCR4 was low in PVT, but was upregulated in media and adventitia at 2 and 3 days, as well as in neointima and adventitia at 7 days. In conclusion, PVT is the primary source of inflammatory CK and CKR early post-angioplasty. Specific sequential patterns of CK- and CKR-synthesis are identified that may regulate phase-specific chemotaxis by spatio-temporally differential expression during coronary response to injury.


Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Quimiocina CCL2/metabolismo , Quimiocinas CXC/metabolismo , Reestenose Coronária/imunologia , Vasos Coronários/lesões , Receptores de Quimiocinas/metabolismo , Cicatrização/imunologia , Animais , Quimiotaxia/imunologia , Tecido Conjuntivo/imunologia , Vasos Coronários/imunologia , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Hibridização In Situ , Inflamação/imunologia , Sus scrofa , Túnica Íntima/imunologia , Túnica Íntima/metabolismo , Túnica Média/imunologia , Túnica Média/metabolismo
20.
Expert Rev Med Devices ; 3(4): 453-62, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16866642

RESUMO

Aortic stenosis (AS) is the most common valvular disease requiring valve replacement with a prevalence of 2-4% in adults greater than or equal to 65 years of age. There is increasing evidence that AS is an active inflammatory process that is highly regulated, displaying multiple hallmarks of atherosclerosis. Clinically, the definite therapy of advanced AS is prosthetic valve replacement. Herein, bioprosthetic tissue valves (BPs) possess superior thromboresistant and hemodynamic properties compared with mechanical valves. However, cusp degeneration and calcification also limit their long-term outcome. The pathogenesis of BP calcification as well as that of native valves is still poorly understood. Recent studies suggest a similar valvular pathology, that underlies both types of valvular degeneration, but also an even more important role of inflammatory and repair processes in the case of BP degeneration.


Assuntos
Valva Aórtica/patologia , Bioprótese , Próteses Valvulares Cardíacas , Valva Aórtica/cirurgia , Calcinose/etiologia , Calcinose/prevenção & controle , Humanos , Inflamação/etiologia , Modelos Biológicos , Falha de Prótese , Fatores de Risco , Resultado do Tratamento
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