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1.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801956

RESUMO

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential.


Assuntos
Envelhecimento , Artérias/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/fisiopatologia , Calcificação Vascular/fisiopatologia , Rigidez Vascular/fisiologia , Artérias/efeitos dos fármacos , Artérias/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Rigidez Vascular/efeitos dos fármacos
2.
Actual. osteol ; 16(2): 140-153, mayo.-ago. 2020. ilus, graf
Artigo em Espanhol | LILACS | ID: biblio-1129814

RESUMO

La osteoporosis y las enfermedades cardiovasculares son patologías prevalentes en mujeres posmenopáusicas. La calcificación vascular es un proceso en el que se produce una distorsión de la arquitectura natural del tejido arterial con una transformación símil osteogénica. La fisiología vascular y la osteogénesis (formación y remodelación ósea) comparten una complejidad metabólica y funcional crítica, que ha sido poco explorada en forma conjunta, lo que ha impulsado la concepción del Eje Óseo-Vascular como nueva área de investigación, con una visión de estudio integradora con la finalidad de identificar vínculos entre ambos sistemas. En virtud de la controversia planteada sobre los riesgos/beneficios de la terapia de reemplazo hormonal para prevenir enfermedades asociadas a la menopausia, se ha incentivado la búsqueda de nuevas opciones de tratamiento. Los fitoestrógenos, como compuestos nutracéuticos, surgen como una potencial alternativa terapéutica. En particular, las isoflavonas presentan gran analogía estructural con el estrógeno humano 17ß-estradiol, lo que les permite unirse al receptor de estrógenos e inducir acciones estrogénicas tanto en células animales como humanas. Basado en la experiencia propia como en lo reportado en la bibliografía, este artículo analiza la información disponible sobre las acciones vasculares y óseas de los fitoestrógenos (específicamente la isoflavona genisteína), con una visión de ciencia traslacional. Es de esperar que los avances en el conocimiento derivado de la ciencia básica, en un futuro cercano, pueda contribuir a decisiones clínicas a favor de promover terapias naturales de potencial acción dual, para la prevención de enfermedades de alta prevalencia y significativo costo social y económico para la población. (AU)


Osteoporosis and cardiovascular diseases are prevalent diseases in postmenopausal women. Vascular calcification is a cellmediated process that leads to the loss of the natural architecture of the arterial vessels due to osteogenic transdifferentiation of smooth muscle cells, and matrix mineralization. Vascular physiology and osteogenesis (bone formation and remodeling) share a critical metabolic and functional complexity. Given the emerging integrative nature of the bonevascular axis, links between both systems are a matter of ongoing interest. In view of the controversy stated about the risks/benefits of hormone replacement therapy to prevent diseases associated with menopause, phytoestrogens arise as a potential natural therapeutic alternative. In particular, isoflavones have a strong structural analogy with the human estrogen 17ß-estradiol, that allows them to bind to the estrogen receptor and induce estrogenic actions in animal and human cells. Based in on our own experience and the information available in the literature, in this paper we provide an overview of the role of phytoestrogens on vascular and bone tissues, with focus on Genistein actions. We wish that the basic knowledge acquired may contribute to guide clinical decisions for the promotion of natural therapies for the treatment of diseases that conspire against human health. (AU)


Assuntos
Humanos , Masculino , Feminino , Osteogênese/efeitos dos fármacos , Fitoestrógenos/uso terapêutico , Aterosclerose/tratamento farmacológico , Calcificação Vascular/tratamento farmacológico , Osteogênese/fisiologia , Menopausa , Doenças Cardiovasculares/complicações , Osteoporose Pós-Menopausa , Remodelação Óssea , Genisteína/uso terapêutico , Fitoestrógenos/classificação , Fitoestrógenos/farmacologia , Aterosclerose/fisiopatologia , Estrogênios/biossíntese , Calcificação Vascular/fisiopatologia , Calcificação Vascular/metabolismo
3.
Arterioscler Thromb Vasc Biol ; 40(7): e193-e202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404005

RESUMO

Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.


Assuntos
Envelhecimento/patologia , Artérias/patologia , Aterosclerose/patologia , Dano ao DNA , Estresse Oxidativo , Placa Aterosclerótica , Calcificação Vascular/patologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apatitas/metabolismo , Artérias/efeitos dos fármacos , Artérias/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Senescência Celular , Dano ao DNA/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Osteogênese , Estresse Oxidativo/efeitos dos fármacos , Poli Adenosina Difosfato Ribose/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
4.
Life Sci ; 253: 117683, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315727

RESUMO

OBJECTIVE: To explore the potential mechanism of KMUP-1 in the vascular calcification of chronic renal failure (CRF) through mediating NO/cGMP/PKG pathway, and provide novel insights into the CRF treatment. METHODS: CRF rats were treated by KMUP-1 with/without L-NNA (a NOS inhibitor) and then performed by ELISA, alizarin red staining, Von Kossa staining, Masson's trichrome, Sirius red staining and CD3 immunohistochemical staining. Simultaneously, vascular smooth muscle cells (VSMCs) were collected from rats to confirm the effect of KMUP-1 on vascular calcification in vitro via NO/cGMP/PKG pathway. Besides, protein and mRNA expressions were determined via Western blotting and qRT-PCR, respectively. RESULTS: CRF rats were elevated in 24-h urine protein, blood urea nitrogen (BUN), serum creatinine, Cys-C levels and inflammatory cytokines. Besides, CRF rats also showed increased calcium content and ALP level with up-regulated mRNA of osteogenic differentiation-related markers. Furthermore, the up-regulated expressions of eNOS and PKG, as well as down-regulated levels of NOx and cGMP were also found in CRF rats. However, renal failure and vascular calcification of CRF were improved significantly by KMUP-1 treatment via activation of NO/cGMP/PKG pathway. Moreover, KMUP-1 treatment attenuated calcified VSMCs, accompanied by the decreases in the calcified nodules, level of calcium and activity of ALP. In addition, either L-NNA treatment for CRF rats or the calcified VSMCs could antagonize the improving effect of KMUP-1. CONCLUSION: KMUP-1 can improve the renal function and vascular calcification in CRF rats at least in part by activating NO/cGMP/PKG pathway.


Assuntos
Falência Renal Crônica/tratamento farmacológico , Miócitos de Músculo Liso/efeitos dos fármacos , Piperidinas/farmacologia , Calcificação Vascular/tratamento farmacológico , Xantinas/farmacologia , Animais , Cálcio/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Falência Renal Crônica/fisiopatologia , Masculino , Miócitos de Músculo Liso/patologia , Óxido Nítrico/metabolismo , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Calcificação Vascular/patologia
5.
Arch Med Res ; 51(3): 215-223, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111501

RESUMO

OBJECTIVE: Vascular calcification is commonly observed in atherosclerosis and diabetes. The renin-angiotensin II system is associated with the regulation of arterial stiffening. The aim of this study was to examine whether the angiotensin-converting enzyme inhibitors captopril attenuates artery calcification. METHODS: The rat model of arterial calcification was established by a combination of warfarin and vitamin K1. Two weeks after the induction of arterial calcification, captopril treatment was initiated. One week after captopril treatment, aortic arteries were examined to determine the calcification morphology and the connexin 43 expression. Matrix Gla protein (MGP), receptor activator of nuclear factor-κB ligand (RANKL) and extracellular regulated protein kinase (ERK) pathways were examined. RESULTS: The morphology of the calcified arteries was significantly attenuated after captopril treatment. Consistently, captopril inhibited the increased connexin 43 expression and enhanced the decreased MGP expression in calcification arteries. Furthermore, captopril enhanced the decreased SM22 expression in calcified arteries by fluorescence assay. Finally, the calcification arteries increased the p38, p-ERK and RANKL expression, which were downregulated by captopril treatment. CONCLUSIONS: We concluded that captopril attenuated the increased connexin 43 expression and enhanced the MGP and SM22 expression levels, which are associated with the inactivation of p-ERK, p38 and RANKL pathways in rat aortic arteries.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Conexina 43/metabolismo , Calcificação Vascular/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Animais , Artérias/patologia , Aterosclerose/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Regulação para Baixo , Proteínas da Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina , Regulação para Cima , Vitamina K 1/toxicidade , Varfarina/toxicidade
6.
Nat Commun ; 11(1): 721, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024848

RESUMO

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.


Assuntos
Fosfatos de Inositol/química , Fosfatos de Inositol/farmacologia , Calcificação Vascular/tratamento farmacológico , 6-Fitase/metabolismo , Adenina/efeitos adversos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Difusão Dinâmica da Luz , Etilenoglicol/química , Humanos , Injeções Subcutâneas , Fosfatos de Inositol/farmacocinética , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos Sprague-Dawley , Uremia/tratamento farmacológico , Uremia/fisiopatologia , Calcificação Vascular/induzido quimicamente , Difração de Raios X
7.
Am J Cardiol ; 125(6): 835-839, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31980142

RESUMO

The prognostic utility of coronary artery calcium (CAC) for individuals taking statins is unclear. We hypothesized that CAC remains associated with atherosclerotic cardiovascular disease (ASCVD) events in individuals using statins at baseline or among those started on statin at follow-up. The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6,814 participants who were enrolled between 2000 and 2002 and were free of clinical ASCVD at baseline. Four follow-up visits were conducted in 2002 to 2004, 2004 to 2006, 2005 to 2007, and 2010 to 2012. CAC was assessed at baseline and follow-up using either an electron-beam CT scanner or a multidetector CT system. Statin use at baseline and follow up was self-reported. Among 6,811 participants with complete information on statin use, mean age was 62 (SD = 10) years, 53% were women, 38% white, 12% Chinese-American, 28% African American, and 22% Hispanic. In multivariable analyses, CAC >0 was associated with a significantly higher risk of ASCVD events regardless of baseline or incident statin use. For example, hazard ratios (95% confidence interval) for the association between CAC >0 and ASCVD were 2.46 (1.41, 4.28) for baseline statin users, 2.08 (1.68, 2.57) for baseline-statin nonusers, and 2.21 (1.56, 3.15) for those started on a statin at follow-up. In conclusion, current statin use does not weaken the prognostic utility of CAC. CAC is associated with incident ASCVD regardless of baseline or incident statin use.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Grupos Étnicos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Calcificação Vascular/tratamento farmacológico , Idoso , Estudos de Coortes , Doença da Artéria Coronariana/etnologia , Comparação Transcultural , Feminino , Seguimentos , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Análise Multivariada , Prognóstico , Fatores de Risco , Tomografia Computadorizada por Raios X , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/etnologia
8.
Nephrol Dial Transplant ; 35(1): 162-169, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31764989

RESUMO

BACKGROUND: Sodium thiosulphate (NaTS) is mostly used in haemodialysis (HD) patients with calcific uraemic arteriolopathy. This double-blind, randomized, placebo-controlled study assessed the effect of NaTS on progression of cardiovascular calcifications in HD patients. METHODS: From 65 screened patients, we recruited 60 patients with an abdominal aorta Agatston calcification score ≥100. Thirty patients were randomized to receive NaTS 25 g/1.73 m2 and 30 patients to receive 100 mL of 0.9% sodium chloride intravenously during the last 15 min of HD over a period of 6 months. The primary endpoint was the absolute change of the abdominal aortic calcification score. RESULTS: The abdominal aortic calcification score and calcification volume of the abdominal aorta increased similarly in both treatment groups during the trial. As compared with the saline group, patients receiving NaTS exhibited a reduction of their iliac artery calcification score (-137 ± 641 versus 245 ± 755; P = 0.049), reduced pulse wave velocity (9.6 ± 2.7 versus 11.4 ± 3.6; P = 0.000) and a lower carotid intima-media thickness (0.77 ± 0.1 versus 0.83 ± 00.17; P = 0.033) and had better preservation of echocardiographic parameters of left ventricular hypertrophy. No patient of the NaTS group developed new cardiac valve calcifications during the trial as compared with 8 of 29 patients in the saline group. By univariate analysis, NaTS therapy was the only predictor of not developing new valvular calcifications. No adverse events possibly related to NaTS infusion were noted. CONCLUSIONS: While NaTS failed to retard abdominal aortic calcification progress, it positively affected calcification progress in iliac arteries and heart valves as well as several other cardiovascular functional parameters.


Assuntos
Antioxidantes/uso terapêutico , Aorta Abdominal/efeitos dos fármacos , Falência Renal Crônica/complicações , Tiossulfatos/uso terapêutico , Calcificação Vascular/tratamento farmacológico , Aorta Abdominal/patologia , Espessura Intima-Media Carotídea , Progressão da Doença , Método Duplo-Cego , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Calcificação Vascular/etiologia , Calcificação Vascular/patologia
9.
Ann Vasc Surg ; 63: 193-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31626934

RESUMO

BACKGROUND: The purpose of this study was to evaluate the factors associated with asymptomatic splenic artery aneurysm (SAA) dilatation. METHODS: Among patients with SAA admitted to our department from 2001 to 2018, 70 lesions in 59 patients were selected and analyzed retrospectively. There were no cases of rupture or pregnancy in the follow-up period. We defined egg-shell appearance as SAA with >75% calcification of the outer shell. We measured the dilatation rate (mm/year) and evaluated the comorbidity and anatomical factors using univariate and multiple linear regression models. Post-hoc multiple linear regression models were fitted to evaluate the possible interactions. RESULTS: The mean age was 61.4 years (range 35-85 years), and the initial aneurysm diameter was 15.1 mm (range 3-47 mm). The mean dilatation rate was 0.26 mm/year (range 0-3.2 mm/year) during the follow-up period (average 4.6 years). Univariate analysis revealed that, portal hypertension (PHT) (P = 0.0003), egg-shell appearance (P = 0.007), and aneurysm diameter > 20 mm (P = 0.05) were significantly associated with the dilatation rate. Multivariate analysis revealed that egg-shell appearance was found to be an independent inverse risk factor of dilatation rate (P = 0.006). The multivariate analysis, including interaction terms, revealed a stronger effect of PHT and diameter >20 mm in cases with no egg-shell appearance (P = 0.08 and P = 0.05 for interactions, respectively). CONCLUSIONS: The egg-shell appearance of SAA was an independent inverse risk factor affecting the SAA dilatation rate. The dilatation rates in the case of PHT and diameter >20 mm were restricted in the presence of the egg-shell appearance.


Assuntos
Aneurisma Roto/etiologia , Aneurisma/complicações , Artéria Esplênica , Calcificação Vascular/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma/diagnóstico por imagem , Aneurisma Roto/diagnóstico por imagem , Doenças Assintomáticas , Dilatação Patológica , Feminino , Humanos , Hipertensão Portal/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Artéria Esplênica/diagnóstico por imagem , Calcificação Vascular/tratamento farmacológico
10.
Circulation ; 141(9): 728-739, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31707860

RESUMO

BACKGROUND: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS: The mean change in coronary artery calcium volume score was 11% (95% CI, 7-15) for the combined SNF472 dose group and 20% (95% CI, 14-26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5-24] versus 98% [95% CI, 77-123]; P<0.001) but not in the thoracic aorta (23% [95% CI, 16-30] versus 28% [95% CI, 19-38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02966028.


Assuntos
Valva Aórtica/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Doenças das Valvas Cardíacas/tratamento farmacológico , Falência Renal Crônica/terapia , Ácido Fítico/administração & dosagem , Diálise Renal , Calcificação Vascular/tratamento farmacológico , Idoso , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/metabolismo , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/mortalidade , Progressão da Doença , Método Duplo-Cego , Durapatita/metabolismo , Europa (Continente) , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/mortalidade , Humanos , Infusões Intravenosas , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Ácido Fítico/efeitos adversos , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/metabolismo , Calcificação Vascular/mortalidade
11.
Vascul Pharmacol ; 125-126: 106636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31881276

RESUMO

Vascular calcification (VC) is an independent cardiovascular event and also a complication commonly found in chronic kidney disease (CKD) and diabetic patients. The mechanisms underpinning pathophysiology of VC is yet to be fully understood. Nevertheless, certain processes are generally believed to participate in its onset and progression. VC pathology is characterized by disequilibrium in the amount of natural inhibitors and active inducers of VC process. The imbalance may favor ectopic deposition of calcium-phosphate in form of hydroxyapatite in media or intima tunica compartments of blood vessels. This eventually could trigger phenotypic switch of smooth muscle cells to osteoblasts related cells. Thus, VSMC phenotypic trans-differentiation is currently considered as one of the hallmarks of VC. At the moment, there is no approved treatment. Fibroblast growth factors (FGFs) are a protein family that participates in varieties of biological processes. More recently, FGF21 seems to be gaining more attention with recent findings showing its anti-calcifying efficacy. In this review, the aim is to point out specific processes involved in VC and also to highlight the participation of FGF21 in the pathology of vascular calcification.


Assuntos
Transdiferenciação Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteoblastos/metabolismo , Osteogênese , Calcificação Vascular/metabolismo , Animais , Transdiferenciação Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteogênese/efeitos dos fármacos , Fenótipo , Transdução de Sinais , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/patologia
12.
Adv Chronic Kidney Dis ; 26(6): 484-490, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31831126

RESUMO

Calciphylaxis is a rare disorder of poor prognosis that can lead to intense, painful lesions involving the skin and subcutaneous tissue. Although mostly described in dialysis patients, it can affect patients with normal kidney function. The diagnosis of calciphylaxis is complicated by the absence of a gold standard marker of disease such as a clear histopathological finding. Late diagnosis and advanced lesions can significantly shorten life expectancy. Calciphylaxis wounds can have a major influence on the quality of life of patients, usually due to the immense unbearable pain these patients suffer from. The management of calciphylaxis mainly comprises aggressive wound care and symptomatic management. Therapeutic options are few and far between and are limited to off-label uses. Recent understanding of the pathogenesis of lesions has enabled development of novel therapeutic options, some of which are being studied in clinical trials (sodium thiosulfate, vitamin K). Vascular calcification and thrombosis underlie development of these lesions and research has been aimed at studying drugs that counteract such processes. Future research is required to establish clear causal pathways and improve on the treatment options currently available to patients.


Assuntos
Calciofilaxia/diagnóstico , Calciofilaxia/terapia , Calcificação Vascular/tratamento farmacológico , Calciofilaxia/complicações , Quelantes/uso terapêutico , Humanos , Falência Renal Crônica/terapia , Microvasos , Manejo da Dor , Diálise Renal , Tiossulfatos/uso terapêutico , Trombofilia/tratamento farmacológico , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Ferimentos e Lesões/etiologia , Ferimentos e Lesões/terapia
13.
Biomed Res Int ; 2019: 3139496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886199

RESUMO

Background: Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. The wingless-type MMTV integration site family member 1 (Wnt1)/ß-catenin pathway is associated with cardiovascular calcification. This study aimed to explore whether melatonin could attenuate VSMC calcification through regulating the Wnt1/ß-catenin signaling pathway. Methods: The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red Staining. Calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure the expression of runt-related transcription factor 2 (Runx2), α-smooth muscle actin (α-SMA), and cleaved caspase-3. Results: Melatonin markedly ameliorated calcium deposition and ALP activity. Runx2 and cleaved caspase-3 were found to be reduced and α-SMA was found to be increased by melatonin, together with a decrease in apoptosis. Immunofluorescence assay revealed a lower Runx2 protein level in the melatonin group. Melatonin treatment significantly decreased the expression of Wnt1 and ß-catenin. Treatment with lithium chloride or transglutaminase 2 abrogated the protective effects of melatonin. Conclusion: Melatonin can attenuate ß-GP-induced VSMC calcification through the suppression of Wnt1/ß-catenin system.


Assuntos
Glicerofosfatos/efeitos adversos , Melatonina/farmacologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Calcificação Vascular , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt1/metabolismo , Animais , Glicerofosfatos/farmacologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , beta Catenina/metabolismo
14.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775364

RESUMO

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7-15 in the presence of high Pi (1.30 ± 0.03 vs 0.61 ± 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7-11, decreased apoptotic cell number (17.3 ± 2.6 vs 11.6 ± 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7-15 (3.8 ± 0.2 vs 2.3 ± 0.3 and 4.0 ± 0.3 vs 2.2 ± 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9-14 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9-15 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H2O2-induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cálcio/toxicidade , Compostos Férricos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Fosfatos/toxicidade , Calcificação Vascular/tratamento farmacológico , Animais , Células Cultivadas , Músculo Liso Vascular/patologia , Ratos , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/patologia
15.
Prog Cardiovasc Dis ; 62(5): 423-430, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31715194

RESUMO

The 2018 and 2019 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of so-called "risk-enhancing factors" in borderline to intermediate risk individuals. These include high-risk race/ethnicity (e.g. South Asian origin), chronic kidney disease, a family history of premature ASCVD, the metabolic syndrome, chronic inflammatory disorders (e.g. rheumatoid arthritis [RA], psoriasis, or chronic human immunodeficiency virus [HIV]), and conditions specific to women, among others. Studies suggest, however, that risk may be highly heterogeneous within these subgroups. The AHA/ACC guidelines also recommend consideration of coronary artery calcium (CAC) scoring for further risk assessment in borderline to intermediate risk individuals in whom management is uncertain. Although the combination of risk enhancing factors and CAC burden (together with Pooled Cohort estimates) may lead to more accurate ASCVD risk assessment, few publications have closely examined the interplay between risk enhancing factors and CAC scoring for personalized risk estimation. Our aim is to review the relevant literature in this area. Although further research is clearly needed, CAC assessment seems a highly valuable option to inform individualized ASCVD risk management in these important, often highly heterogeneous patient subgroups.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Prevenção Primária/normas , Calcificação Vascular/tratamento farmacológico , Fatores Etários , Tomada de Decisão Clínica , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Masculino , Seleção de Pacientes , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologia
16.
J. bras. nefrol ; 41(3): 345-355, July-Sept. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1040247

RESUMO

ABSTRACT Introduction: There is evidence that aldosterone plays a role in the pathogenesis of vascular calcification. The aim of this study was to evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, on the progression of coronary calcification (CC) in peritoneal dialysis patients and to identify the factors involved in this progression. Methods: Thirty-three patients with a coronary calcium score (CCS) ≥ 30, detected through multi-detector computed tomography (MDCT) and expressed in Agatston units, were randomly assigned to a group receiving 25mg spironolactone per day for 12 months (spironolactone group) and a control group not receiving this drug. The primary outcome was a percentage change in CCS from baseline to end of the study (relative progression), when a further MDCT was conducted. Patients who had progression of CC were compared with those who did not progress. Results: Sixteen patients, seven in the spironolactone group and nine in the control group, concluded the study. The relative progression of the CCS was similar in both groups, 17.2% and 27.5% in the spironolactone and control groups respectively. Fifty-seven percent of the treated patients and 67% of those in the control group presented progression in the CC scores (p = 0.697). Progressor patients differed from non-progressors because they presented higher levels of calcium and low-density lipoprotein cholesterol and lower levels of albumin. Conclusion: In peritoneal dialysis patients, spironolactone did not attenuate the progression of CC. However, large-scale studies are needed to confirm this observation. Disorders of mineral metabolism and dyslipidemia are involved in the progression of CC.


RESUMO Introdução: Existem evidências de que a aldosterona exerça um papel na patogênese da calcificação vascular. O objetivo deste estudo foi avaliar o efeito da espironolactona, um antagonista do receptor mineralocorticoide, na progressão da calcificação coronariana (CC) de pacientes em diálise peritoneal, e identificar os fatores envolvidos nessa progressão. Métodos: Trinta e três pacientes com escore de cálcio coronariano (ECC) ≥ 30, detectado por tomografia computadorizada com múltiplos detectores (TCMD) e expresso em unidades de Agatston, foram randomizados para um grupo que recebeu 25 mg de espironolactona por dia durante 12 meses (grupo espironolactona) e um grupo controle que não recebeu este medicamento. O desfecho primário foi a mudança percentual do ECC do início para o final do estudo (progressão relativa), quando uma nova TCMD foi realizada. Os pacientes que tiveram progressão de CC foram comparados com aqueles que não progrediram. Resultados: Dezesseis pacientes, sete no grupo espironolactona e nove no grupo controle, concluíram o estudo. A progressão relativa do ECC foi semelhante nos dois grupos, 17,2% e 27,5% nos grupos espironolactona e controle, respectivamente. Cinquenta e sete por cento dos pacientes tratados e 67% daqueles no grupo controle apresentaram progressão nos escores de CC (p = 0,697). Os pacientes progressores diferiram dos não progressores porque apresentaram níveis séricos mais elevados de cálcio e LDL-colesterol e menores níveis de albumina. Conclusão: Em pacientes em diálise peritoneal, a espironolactona não atenuou a progressão da CC. No entanto, estudos em grande escala são necessários para confirmar essa observação. Distúrbios do metabolismo mineral e dislipidemia estão envolvidos na progressão da CC.


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Espironolactona/uso terapêutico , Diálise Peritoneal , Progressão da Doença , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/sangue , Espironolactona/administração & dosagem , Tomógrafos Computadorizados , Projetos Piloto , Cálcio/sangue , Estudos Prospectivos , Seguimentos , Resultado do Tratamento , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Insuficiência Renal Crônica/terapia , Perda de Seguimento , Calcificação Vascular/patologia , Calcificação Vascular/diagnóstico por imagem , Albumina Sérica Humana/análise , LDL-Colesterol/sangue
17.
J Cell Biochem ; 120(12): 19660-19672, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407397

RESUMO

BACKGROUND: In this study, we established both an animal model and a cellular model of hyperuricemia (HUC). Subsequently, we treated these models with allopurinol (ALLO) to study the effect of uric acid (UA) and ALLO on the differentiation and proliferation of osteoblasts and vascular smooth muscle cells (VSMC). METHODS: Western Blot, immunohistochemistry assay, and real-time polymerase chain reaction were conducted to measure the changes in the expression of differentiation-related factors in osteoblasts and VSMCs in HUC and HUC+ALLO groups. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry were utilized to observe the changes in the proliferation of osteoblasts in HUC and HUC+ALLO groups. Von Kossa staining was performed along with calcium content measurement to investigate the effect of HUC/ALLLO on vascular calcification. RESULTS: In this study, the levels of Wnt3a and differentiation-related factors, including Runx2, Sp7, Ibsp, Bglap, Dmp1, and Col1a1, were all evidently decreased in HUC rats, while the presence of ALLO increased the levels of above factors. In addition, the viability of osteoblasts was reduced while their apoptosis was elevated in the HUC group, and ALLO treatment reduced the apoptosis and increased the viability of osteoblasts to a certain extent. Moreover, HUC elevated the levels of Wnt3a, Runx2, Sp7, Bglap, Col1a1, SM22a, and Acta2 in VSMCs of HUC rats, leading to greatly increased calcium content and obvious vascular calcification. In contrary, ALLO treatment reduced the effect of HUC. Furthermore, the effect of UA and ALLO on osteoblasts and VSMCs was also validated in cellular models treated with monosodium urate (MSU) crystals or MSU+ALLO. CONCLUSIONS: HUC can suppress the differentiation and proliferation of osteoblasts while promoting the differentiation of VSMCs both in vivo and in vitro. The treatment by ALLO exhibited a therapeutic effect on HUC by promoting the differentiation and proliferation of osteoblasts while reducing vascular calcification.


Assuntos
Doenças Ósseas Metabólicas/patologia , Diferenciação Celular , Proliferação de Células , Gota/patologia , Hiperuricemia/fisiopatologia , Músculo Liso Vascular/patologia , Osteoblastos/patologia , Calcificação Vascular/patologia , Alopurinol/farmacologia , Animais , Apoptose , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Gota/tratamento farmacológico , Gota/etiologia , Gota/metabolismo , Supressores da Gota/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo
18.
Semin Dial ; 32(6): 553-561, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31464003

RESUMO

Patients with chronic kidney disease (CKD) have a predisposition to develop vascular calcification due to dysregulated homeostatic mechanisms, which lead to an imbalance in the circulatory promoters and inhibitors of vascular calcification, leading to a net calcification stress. These factors promote ectopic calcification and induce vascular smooth muscle cells to undergo osteogenic differentiation and actively calcify the vascular media. The article summarizes clinically relevant pathogenic mechanisms of vascular calcification in patients with CKD and in dialysis patients and summarizes novel therapeutic interventions. In addition to the management of traditional cardiovascular risk factors, patients with CKD-mineral and bone disorder need close attention in the management of the mineral metabolism to prevent adverse effects on the bone and vascular compartments. This article reviews current evidence and therapeutic guidelines in the management of mineral metabolism in CKD and dialysis.


Assuntos
Calciofilaxia/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Falência Renal Crônica/epidemiologia , Diálise Renal/efeitos adversos , Calcificação Vascular/epidemiologia , Calcificação Vascular/patologia , Calciofilaxia/tratamento farmacológico , Calciofilaxia/fisiopatologia , Calcitriol/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Cinacalcete/administração & dosagem , Comorbidade , Feminino , Humanos , Incidência , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Prognóstico , Diálise Renal/métodos , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Calcificação Vascular/tratamento farmacológico , Vitamina D/administração & dosagem
19.
J Bras Nefrol ; 41(3): 345-355, 2019 Aug 15.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31419271

RESUMO

INTRODUCTION: There is evidence that aldosterone plays a role in the pathogenesis of vascular calcification. The aim of this study was to evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, on the progression of coronary calcification (CC) in peritoneal dialysis patients and to identify the factors involved in this progression. METHODS: Thirty-three patients with a coronary calcium score (CCS) ≥ 30, detected through multi-detector computed tomography (MDCT) and expressed in Agatston units, were randomly assigned to a group receiving 25mg spironolactone per day for 12 months (spironolactone group) and a control group not receiving this drug. The primary outcome was a percentage change in CCS from baseline to end of the study (relative progression), when a further MDCT was conducted. Patients who had progression of CC were compared with those who did not progress. RESULTS: Sixteen patients, seven in the spironolactone group and nine in the control group, concluded the study. The relative progression of the CCS was similar in both groups, 17.2% and 27.5% in the spironolactone and control groups respectively. Fifty-seven percent of the treated patients and 67% of those in the control group presented progression in the CC scores (p = 0.697). Progressor patients differed from non-progressors because they presented higher levels of calcium and low-density lipoprotein cholesterol and lower levels of albumin. CONCLUSION: In peritoneal dialysis patients, spironolactone did not attenuate the progression of CC. However, large-scale studies are needed to confirm this observation. Disorders of mineral metabolism and dyslipidemia are involved in the progression of CC.


Assuntos
Progressão da Doença , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Diálise Peritoneal , Espironolactona/uso terapêutico , Calcificação Vascular/sangue , Calcificação Vascular/tratamento farmacológico , Idoso , Cálcio/sangue , LDL-Colesterol/sangue , Feminino , Seguimentos , Humanos , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Insuficiência Renal Crônica/terapia , Albumina Sérica Humana/análise , Espironolactona/administração & dosagem , Tomógrafos Computadorizados , Resultado do Tratamento , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologia
20.
Med Hypotheses ; 132: 109354, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31421415

RESUMO

Vascular calcification is a recognised source of morbidity among mid-age and elderly subjects. Its development follows classical mineralisation pathways, inhibited by acidosis. It is known that the final mechanism of tissue mineralization involves three processes, all of which are highly pH dependent. Calcium interacts with phosphate in its trivalent form, but this step is inhibited by pyrophosphate, itself a source of phosphate when hydrolysed by alkaline phosphatase. Separately, matrix vesicles create nucleation sites and may indirectly disrupt vascular smooth muscle cells. Metabolic acidosis acts at every point to delay mineralization. The diuretic acetazolamide creates a sustained mild acidosis with some phosphate loss and, though usually ineffective in the experimental model, has been used with success in certain clinical conditions. We suggest that acetazolamide, well studied and tolerated, might inhibit progression of vascular calcification in subjects at risk through its dual action of lowering tissue pH and local phosphate concentration.


Assuntos
Acetazolamida/farmacologia , Placa Aterosclerótica/dietoterapia , Placa Aterosclerótica/patologia , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/patologia , Acidose , Idoso , Fosfatase Alcalina/metabolismo , Cálcio/metabolismo , Progressão da Doença , Humanos , Concentração de Íons de Hidrogênio , Inflamação , Rim/efeitos dos fármacos , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosfatos/metabolismo
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