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1.
Angiogenesis ; 25(4): 535-546, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35802311

RESUMO

BACKGROUND: Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. OBJECTIVES: We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. METHODS: The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. RESULTS: The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm2 at to 109 mm2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. CONCLUSIONS: Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015.


Assuntos
Isquemia Crônica Crítica de Membro , Qualidade de Vida , Amputação Cirúrgica , Humanos , Isquemia , Neovascularização Patológica , Estudos Prospectivos , Resultado do Tratamento
2.
Platelets ; 33(5): 735-742, 2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34672911

RESUMO

Platelet activation in the hemodialysis (HD) circuit often causes thrombocytopenia. However, its clinical and pathophysiological significance has rarely been explored. Herein, we investigated the predictive value of thrombocytopenia for cardiovascular events (CVE) in maintenance HD patients and attempted to explore its mechanistic background considering recent knowledge of platelet dynamics. We conducted a retrospective cohort study on HD patients with the composite primary endpoint of predicting CVE, i.e., myocardial infarction, ischemic stroke, and cardiovascular death. Baseline clinical data were analyzed and explored. Multivariate Cox regression analysis showed that platelet decrease was independently associated with CVE. Thrombocytopenia was correlated with the disuse of antiplatelet therapy (APT) and macrocytosis. These findings are possibly associated with platelet activation and senescent hematopoiesis. The prognostic significance of thrombocytopenia was more prominent in patients undergoing APT, implying the presence of APT-resistant platelets in such patients. To fully explain these results, we hypothesized that HD-activated platelets induce the biological aging of hematopoiesis, which is presumably extramedullary in the lung, where activated platelets could deliver massive amounts of inflammatory cytokines and reactive oxidative species. This results in the production of qualitatively altered and hyper-reactive platelets, a process that could form a vicious cycle that induces CVE-associated thrombocytopenia. Further investigations focusing on the dynamics of the biological aging of platelets in HD patients are warranted.


Assuntos
Anemia , Trombocitopenia , Plaquetas , Humanos , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Trombocitopenia/complicações
3.
J Arrhythm ; 33(1): 63-65, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28217231

RESUMO

The entirely subcutaneous implantable cardioverter-defibrillator (ICD) system was developed to provide a life-saving defibrillation therapy that does not affect the heart and vasculature. The subcutaneous ICD is preferred over the transvenous ICD for patients with a history of recurrent infection presenting major life-threatening rhythms. In this case report, we describe the first successful intermuscular implantation of a completely subcutaneous ICD in a Japanese patient with pectus excavatum. There were no associated complications with the device implantation or lead positioning. Further, the defibrillation threshold testing did not pose any problem with the abnormal anatomy of the patient.

4.
PLoS One ; 9(6): e100359, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24950189

RESUMO

Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.


Assuntos
Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Proteínas de Ligação ao Cálcio/genética , Senescência Celular/efeitos dos fármacos , Fosfatase 1 de Especificidade Dupla/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Proteínas de Membrana/genética , Camundongos , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Serrate-Jagged , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
5.
Hypertens Res ; 36(10): 859-65, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23719127

RESUMO

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.


Assuntos
Angiotensina II/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Receptores Notch/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Células Cultivadas , Dibenzazepinas/farmacologia , Dipeptídeos/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Músculo Liso Vascular/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Notch/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Arterioscler Thromb Vasc Biol ; 32(8): 1902-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22556331

RESUMO

OBJECTIVE: The central nervous system is thought to influence the regulation of the cardiovascular system in response to humoral and neural signals from peripheral tissues, but our understanding of the molecular mechanisms involved is still quite limited. METHODS AND RESULTS: Here, we demonstrate a central nervous system-mediated mechanism by which brain-derived neurotrophic factor (BDNF) has a protective effect against cardiac remodeling after myocardial infarction (MI). We generated conditional BDNF knockout mice, in which expression of BDNF was systemically reduced, by using the inducible Cre-loxP system. Two weeks after MI was induced surgically in these mice, systolic function was significantly impaired and cardiac size was markedly increased in conditional BDNF knockout mice compared with controls. Cardiomyocyte death was increased in these mice, along with decreased expression of survival molecules. Deletion of the BDNF receptor (tropomyosin-related kinase B) from the heart also led to the exacerbation of cardiac dysfunction after MI. The plasma levels of BDNF were markedly increased after MI, and this increase was associated with the upregulation of BDNF expression in the brain, but not in the heart. Ablation of afferent nerves from the heart or genetic disruption of neuronal BDNF expression inhibited the increase of plasma BDNF after MI and led to the exacerbation of cardiac dysfunction. Peripheral administration of BDNF significantly restored the cardiac phenotype of neuronal BDNF-deficient mice. CONCLUSIONS: These results suggest that BDNF expression is upregulated by neural signals from the heart after MI and then protects the myocardium against ischemic injury.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Encéfalo/fisiologia , Infarto do Miocárdio/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/sangue , Camundongos , Camundongos Knockout , Receptor trkB/fisiologia , Transdução de Sinais , Sístole , Remodelação Ventricular
7.
Cell Metab ; 15(1): 51-64, 2012 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-22225876

RESUMO

Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.


Assuntos
Tecido Adiposo/metabolismo , Insuficiência Cardíaca/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/patologia , Isoproterenol/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pressão , Sistema Nervoso Simpático/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Regulação para Cima
8.
PLoS One ; 6(10): e25487, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22003393

RESUMO

BACKGROUND: Transplantation of mononuclear cells (MNCs) has previously been tested as a method to induce therapeutic angiogenesis to treat limb ischemia in clinical trials. Non-invasive high resolution imaging is required to track the cells and evaluate clinical relevance after cell transplantation. The hypothesis that MRI can provide in vivo detection and long-term observation of MNCs labeled with manganese contrast-agent was investigated in ischemic rat legs. METHODS AND FINDINGS: The Mn-labeled MNCs were evaluated using 7-tesla high-field magnetic resonance imaging (MRI). Intramuscular transplanted Mn-labeled MNCs were visualized with MRI for at least 7 and up to 21 days after transplantation in the ischemic leg. The distribution of Mn-labeled MNCs was similar to that of ¹¹¹In-labeled MNCs measured with single-photon emission computed tomography (SPECT) and DiI-dyed MNCs with fluorescence microscopy. In addition, at 1-2 days after transplantation the volume of the site injected with intact Mn-labeled MNCs was significantly larger than that injected with dead MNCs, although the dead Mn-labeled MNCs were also found for approximately 2 weeks in the ischemic legs. The area covered by CD31-positive cells (as a marker of capillary endothelial cells) in the intact Mn-MNCs implanted site at 43 days was significantly larger than that at a site implanted with dead Mn-MNCs. CONCLUSIONS: The present Mn-enhanced MRI method enabled visualization of the transplanted area with a 150-175 µm in-plane spatial resolution and allowed the migration of labeled-MNCs to be observed for long periods in the same subject. After further optimization, MRI-based Mn-enhanced cell-tracking could be a useful technique for evaluation of cell therapy both in research and clinical applications.


Assuntos
Células da Medula Óssea/citologia , Rastreamento de Células/métodos , Transplante de Células , Cloretos , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês , Animais , Circulação Sanguínea , Cloretos/metabolismo , Meios de Contraste/metabolismo , Membro Posterior/irrigação sanguínea , Isquemia/diagnóstico , Isquemia/metabolismo , Isquemia/fisiopatologia , Isquemia/cirurgia , Cinética , Angiografia por Ressonância Magnética , Masculino , Compostos de Manganês/metabolismo , Microscopia de Fluorescência , Compostos Organometálicos , Oxiquinolina/análogos & derivados , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Wistar , Coloração e Rotulagem , Tomografia Computadorizada de Emissão de Fóton Único
9.
Arterioscler Thromb Vasc Biol ; 31(9): 2000-6, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21680900

RESUMO

OBJECTIVE: Impaired regeneration of endothelial cells (EC) and overactivity of vascular smooth muscle cells (VSMC) are hallmarks of the arterial lesions associated with aging. The occurrence of 2 opposing cellular processes in the same arterial milieu makes pharmaceutical treatment difficult to develop. We previously reported that endothelial expression of a Notch ligand (Jagged1) was reduced in aged animals and that growth of the neointima was enhanced in these animals. METHODS AND RESULTS: Similar to aged animals, Tie2-cre(+) Jagged1(lox/+) mice (with heterologous knockout of Jagged1 in EC) showed exaggerated intimal and medial thickening after carotid artery ligation. Unexpectedly, these mice showed little increase of Jagged1 expression not only in EC but also in VSMC, in contrast to a significant upregulation of Jagged1 in wild-type arteries after ligation. Coculture of VSMC with Jagged1-null EC resulted in the transition of VSMC from the contractile to the synthetic phenotype, along with decreased Jagged1 expression by VSMC. Conversely, overexpression of Jagged1 by EC or VSMC was shown to prevent the unfavorable phenotypic transition of VSMC, under both monoculture and coculture conditions. CONCLUSIONS: These findings suggest a unidirectional effect of Jagged1 on both EC and VSMC that contributes to inhibition of arterial lesions after vascular injury. Our data also indicate that Jagged1 may be a novel therapeutic target for aging-related vascular diseases.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Lesões do Sistema Vascular/patologia , Envelhecimento/patologia , Animais , Artérias Carótidas/patologia , Comunicação Celular , Células Cultivadas , Células Endoteliais/fisiologia , Feminino , Proteína Jagged-1 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptor TIE-2 , Proteínas Serrate-Jagged , Túnica Íntima/patologia
10.
Int J Cardiol ; 150(2): e81-4, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20061038

RESUMO

An asymptomatic 62-year-old female patient with sarcoidosis was referred to our hospital for new-onset right bundle-branch block by electrocardiogram (ECG). She had been diagnosed with sarcoidosis by lymph node biopsy 3 years previously, and followed up by chest X-ray and ECG from then onward. Chest X-ray on admission showed bilateral lymph node enlargement, which was unchanged. Transthoracic echocardiogram showed wall thinning and severe hypokinesis in the basal portion of the left ventricular (LV) posterior-inferior wall, and coronary heart disease was excluded by conventional coronary angiogram. ECG-gated enhanced 320 slice multislice computed tomography revealed contrast defects in the basal portion of the LV posterior-inferior wall with reduced wall thickness in the early phase, which were conversely abnormally enhanced in the late phase, suggesting fibrosis or edema with inflammation. Late gadolinium enhancement in contrast-enhanced magnetic resonance imaging (MRI) was observed in the same region. To evaluate for evidence of inflammation, we performed 67-gallium-citrate scintigraphy, T2-weighted MRI, and fasting 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET). Although the 67-Ga scintigram showed no significant uptake, T2-weighted MRI revealed high intensity images, and fasting 18F-FDG PET identified increased uptake of FDG in the basal portion of the LV posterior-inferior wall, suggesting inflammation. We started corticosteroid therapy, diagnosing her condition as active cardiac sarcoidosis.


Assuntos
Cardiomiopatias/diagnóstico , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Sarcoidose/diagnóstico , Tomografia Computadorizada por Raios X , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos
11.
J Clin Invest ; 120(5): 1506-14, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20407209

RESUMO

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload-induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.


Assuntos
Insulina/metabolismo , Miocárdio/metabolismo , Sístole , Animais , Diabetes Mellitus Tipo 1/sangue , Insuficiência Cardíaca , Hipóxia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pressão , Ratos , Ratos Endogâmicos SHR , Receptor de Insulina/biossíntese , Estresse Mecânico , Regulação para Cima
12.
Circ Res ; 106(2): 391-8, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-19940264

RESUMO

RATIONALE: The axon-guiding molecules known as semaphorins and their receptors (plexins) regulate the vascular pattern and play an important role in the development of vascular network during embryogenesis. Semaphorin (Sema)3E is one of the class 3 semaphorins, and plexinD1 is known to be its receptor. Although these molecules have a role in embryonic vascular development, it remains unclear whether the Sema3E/plexinD1 axis is involved in postnatal angiogenesis. OBJECTIVE: The objective of this study was to elucidate the role of Sema3E/plexinD1 in postnatal angiogenesis. METHODS AND RESULTS: Sema3E inhibited cell growth and tube formation by suppressing the vascular endothelial growth factor (VEGF) signaling pathway. Expression of Sema3E and plexinD1 was markedly upregulated in ischemic limbs of mice (2.5- and 4.5-fold increase for Sema3E and plexinD1, respectively), and inhibition of this pathway by introduction of the plexinD1-Fc gene or disruption of Sema3E led to a significant increase of blood flow recovery (1.6- and 1.5-fold increase for the plexinD1-Fc gene treatment and Sema3E disruption, respectively). Hypoxia activated the tumor suppressor protein p53, thereby upregulating Sema3E expression. Expression of p53 and Sema3E was enhanced in diabetic mice compared with normal mice (2- and 1.3-fold increase for p53 and Sema3E, respectively). Consequently, neovascularization after VEGF treatment was poor in the ischemic tissues of diabetic mice, whereas treatment with VEGF plus plexinD1-Fc markedly improved neovascularization. CONCLUSIONS: These results indicate that inhibition of Sema3E may be a novel strategy for therapeutic angiogenesis, especially when VEGF is ineffective.


Assuntos
Moléculas de Adesão Celular Neuronais/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Semaforinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Western Blotting , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Isquemia , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Oncogênica v-akt/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Semaforinas/genética , Semaforinas/metabolismo , Estreptozocina , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
Circ Cardiovasc Interv ; 2(3): 245-54, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20031722

RESUMO

BACKGROUND: Injection of bone marrow mononuclear cells has been reported to promote neovascularization of ischemic tissues effectively. We found that peripheral blood mononuclear cells were as efficient as bone marrow mononuclear cells for the treatment of limb ischemia in animals and showed that this treatment was feasible and safe in no-option patients with limb ischemia. However, the long-term outcome of such therapy has not been investigated. METHODS AND RESULTS: We retrospectively analyzed the data for 42 patients who were treated between July 2002 and December 2005 by using the log-rank test, the Kaplan-Meier method, and the Cox proportional hazard model. Improvement of ischemic symptoms was observed in 60% to 70% of the patients. The annual rate of major amputation was decreased markedly by treatment. Improvement of ischemic symptoms was less marked in arteriosclerosis obliterans (ASO) patients on dialysis compared with nonhemodialysis ASO or thromboangiitis obliterans patients. Indeed, the survival rate of these patients was lower than that of nonhemodialysis ASO or thromboangiitis obliterans patients. Major adverse events such as death, major amputation, and cardiovascular events occurred mostly in ASO patients, and most of them were on dialysis. There was no significant difference in the cardiovascular event-free rate between responders and nonresponders. The survival rate of younger responders was better than that of nonresponders. CONCLUSIONS: Although this study was not placebo-controlled and these initial results were from a retrospective analysis, injection of peripheral blood mononuclear cells might be safe and potentially effective for the treatment of limb ischemia, but caution is needed when managing ASO patients on dialysis.


Assuntos
Células Endoteliais/transplante , Extremidades/irrigação sanguínea , Isquemia/cirurgia , Neovascularização Fisiológica , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica , Arteriosclerose Obliterante/complicações , Arteriosclerose Obliterante/fisiopatologia , Arteriosclerose Obliterante/cirurgia , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Isquemia/etiologia , Isquemia/mortalidade , Isquemia/fisiopatologia , Estimativa de Kaplan-Meier , Salvamento de Membro , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Modelos de Riscos Proporcionais , Diálise Renal/efeitos adversos , Reoperação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tromboangiite Obliterante/complicações , Tromboangiite Obliterante/fisiopatologia , Tromboangiite Obliterante/cirurgia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
J Exp Med ; 206(7): 1565-74, 2009 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-19546247

RESUMO

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.


Assuntos
Araquidonato 12-Lipoxigenase/imunologia , Araquidonato 15-Lipoxigenase/imunologia , Insuficiência Cardíaca , Inflamação , Miocárdio , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/genética , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Perfilação da Expressão Gênica , Coração/fisiologia , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/imunologia , Humanos , Inflamação/enzimologia , Inflamação/imunologia , Inibidores de Lipoxigenase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/enzimologia , Miocárdio/imunologia , Ratos , Ratos Endogâmicos Dahl , Ratos Wistar , Sódio na Dieta
15.
Arterioscler Thromb Vasc Biol ; 29(6): 889-94, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19286634

RESUMO

OBJECTIVE: Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD(+)-dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood. METHODS AND RESULTS: Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes. CONCLUSIONS: These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.


Assuntos
Diabetes Mellitus Experimental/enzimologia , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/enzimologia , Endotélio Vascular/enzimologia , Glucose/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Aorta/enzimologia , Células Cultivadas , Senescência Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/enzimologia , Angiopatias Diabéticas/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Ativadores de Enzimas/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol , Transdução de Sinais , Sirtuína 1 , Sirtuínas/agonistas , Sirtuínas/genética , Estilbenos/farmacologia , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/metabolismo
16.
Circ Res ; 103(3): 261-8, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18583712

RESUMO

Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs "fine tuning" of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1(+/-) mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1(+/-) Akt1(+/-) mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.


Assuntos
Endotélio Vascular/citologia , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Sobrevivência Celular , Células Cultivadas , Senescência Celular , Endotélio Vascular/fisiologia , Humanos , Isquemia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
17.
Circ Res ; 102(5): 607-14, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18218984

RESUMO

Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element-dependent and the E-box enhancer element-dependent pathways. Both phosphorylation and S-nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.


Assuntos
Envelhecimento/metabolismo , Transtornos Cronobiológicos/fisiopatologia , Óxido Nítrico/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Células Cultivadas , Transtornos Cronobiológicos/tratamento farmacológico , Transtornos Cronobiológicos/etiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Meios de Cultura Livres de Soro/farmacologia , Elementos Facilitadores Genéticos/efeitos dos fármacos , Elementos Facilitadores Genéticos/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Nucleares/genética , Proteínas Circadianas Period , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Fatores de Tempo , Transfecção , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
18.
Ann Vasc Dis ; 1(2): 66-79, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-23555342

RESUMO

There have been great progresses in our knowledge of patho-physiology on various cardiovascular diseases, which enabled us to develop the field of regenerative medicine for previously untreatable patients. Among several strategies in cardiovascular regenerative medicine, cell transplantation is one of the best studied and the best clinically practiced. In this review we will first summarize the mechanisms of cell therapy, and then go through lists of cells and diseases that can be applied. Later we will introduce some of the clinical experiences published so far, with some discussion regarding the problems and perspectives of this novel therapeutics.

19.
Nature ; 446(7134): 444-8, 2007 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-17334357

RESUMO

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.


Assuntos
Baixo Débito Cardíaco/fisiopatologia , Cardiomegalia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Animais , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea , Cardiomegalia/patologia , Circulação Coronária , Progressão da Doença , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Neovascularização Patológica , Proteína Supressora de Tumor p53/genética
20.
Circulation ; 114(9): 953-60, 2006 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-16908765

RESUMO

BACKGROUND: Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined. METHODS AND RESULTS: Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II. CONCLUSIONS: We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.


Assuntos
Senilidade Prematura/fisiopatologia , Angiotensina II/farmacologia , Aterosclerose/fisiopatologia , Músculo Liso Vascular/crescimento & desenvolvimento , Animais , Aorta , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Pressão Sanguínea , Células Cultivadas , Modelos Animais de Doenças , Genes Reporter , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Transfecção
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