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1.
J Cell Physiol ; 232(11): 2985-2995, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28369848

RESUMEN

Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.


Asunto(s)
Anexina A6/metabolismo , Estenosis de la Válvula Aórtica/metabolismo , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Calcinosis/metabolismo , Matriz Extracelular/metabolismo , Vesículas Extracelulares/metabolismo , Hipercalcemia/etiología , Fallo Renal Crónico/complicaciones , Anciano , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Válvula Aórtica/ultraestructura , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , Calcinosis/etiología , Calcinosis/genética , Calcinosis/patología , Calcio/metabolismo , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Matriz Extracelular/ultraestructura , Vesículas Extracelulares/ultraestructura , Femenino , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Hipercalcemia/diagnóstico , Fallo Renal Crónico/diagnóstico , Masculino , Microscopía Electrónica de Transmisión , Mapas de Interacción de Proteínas , Proteómica/métodos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Regulación hacia Arriba
2.
J Cardiovasc Surg (Torino) ; 59(1): 115-120, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28548476

RESUMEN

BACKGROUND: Experimental evidence suggests that blood cardioplegia (BCP) may be superior to cold crystalloid cardioplegia (CCP) for myocardial protection. However, robust clinical data are lacking. We compared postoperative outcome of patients undergoing aortic valve replacement (AVR) using cold anterograde-retrograde intermittent BCP versus anterograde (CCP). METHODS: Adult consecutive isolated AVR performed between April 2006 and February 2011 at the Royal Infirmary Hospital of Edinburgh were retrospectively analyzed. The use of anterograde CCP was compared with that of intermittent anterograde-retrograde cold BCP. End points were intra-operative mortality, 30-day hospital re-admission, need for RBC or platelet transfusion, mechanical ventilation time and renal failure. RESULTS: Of total 774 cases analyzed, 592 cases of BCP and 182 cases of CCP were identified. Demographics did not differ between groups (mean age: 67±12 years in CCP and 69±12 years in BCP). Groups (BCP vs. CCP) were indistinguishable (P>0.05, not significant) based on: average aortic cross clamp time 77.01±14.47 vs. 75.78±18.78 minutes, cardiopulmonary bypass time 104.07±43.70 vs. 100.34±25.90 minutes, surgery time 190.53±61.80 vs. 204.04±51.09 minutes and postoperative total blood consumption 1.38±2.11 vs. 1.61±2.4 units. The percentage of patients who required platelets' transfusion was similar: 12.8% BCP and 18.7% CCP (Fisher's exact test, P=0.053). Prevalence of respiratory failure was lower in BCP than in CCP: 2.6% vs. 6.3% (P=0.028). Admission time (days) at ICU was 3.63± 21.90 in BCP and 3.07±8.04 in CCP (not significant). Intra-hospital mortality, 30-day hospital re-admission, renal failure, sepsis, wound healing and stroke did not differ between groups. CONCLUSIONS: BCP was strictly not superior to CCP in every aspect. In particular it was definitely not superior in terms of postoperative ventricular function. Our results question the absolute superiority of BCP over CCP in terms of hard outcomes. Likelihood of serious complications should be considered to improve risk profile of patients before choosing a cardioplegic solution.


Asunto(s)
Válvula Aórtica/cirugía , Soluciones Cardiopléjicas/uso terapéutico , Paro Cardíaco Inducido/métodos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Soluciones Isotónicas/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Anciano , Transfusión de Componentes Sanguíneos/estadística & datos numéricos , Puente Cardiopulmonar , Soluciones Cristaloides , Femenino , Implantación de Prótesis de Válvulas Cardíacas/mortalidad , Mortalidad Hospitalaria , Humanos , Masculino , Readmisión del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/mortalidad , Estudios Retrospectivos , Resultado del Tratamiento
3.
Sci Rep ; 6: 24807, 2016 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-27095121

RESUMEN

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.


Asunto(s)
Músculo Liso Vascular/metabolismo , Receptores Androgénicos/metabolismo , Testosterona/metabolismo , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Animales , Apoptosis/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Miocitos del Músculo Liso/metabolismo , Osteogénesis/genética , Receptores Androgénicos/genética , Testosterona/farmacología , Calcificación Vascular/genética
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