ABSTRACT
Vascular calcification (VC) is associated with increased cardiovascular mortality in aging, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM) and atherosclerosis. TNF-like weak inducer of apoptosis (TWEAK) recently emerged as a new biomarker for the diagnosis and prognosis of cardiovascular diseases. TWEAK binding to its functional receptor Fn14 was reported to promote several steps of atherosclerotic plaque progression. However, no information is currently available on the role of TWEAK/Fn14 on the development of medial calcification, which is highly prevalent in aging, CKD and T2DM. This study explored the involvement of TWEAK in human vascular smooth muscle cells (h-VSMCs) calcification in vitro. We report that TWEAK binding to Fn14 promotes inorganic phosphate-induced h-VSMCs calcification, favors h-VSMCs osteogenic transition, decreasing acta2 and myh11 and increasing bmp2 mRNA and tissue non-specific alkaline phosphatase (TNAP), and increases MMP9 activity. Blockade of the canonical NFκB pathway reduced by 80% TWEAK pro-calcific properties and decreased osteogenic transition, TNAP and MMP9 activity. Blockade of non-canonical NFκB signaling by a siRNA targeting RelB reduced by 20% TWEAK pro-calcific effects and decreased TWEAK-induced loss of h-VSMCs contractile phenotype and MMP9 activity, without modulating bmp2 mRNA or TNAP activity. Inhibition of ERK1/2 activation by a MAPK kinase inhibitor did not influence TWEAK pro-calcific properties. Our results suggest that TWEAK/Fn14 directly favors inorganic phosphate-induced h-VSMCs calcification by activation of both canonical and non-canonical NFκB pathways. Given the availability of neutralizing anti-TWEAK strategies, our study sheds light on the TWEAK/Fn14 axis as a novel therapeutic target in the prevention of VC.
Subject(s)
Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Phosphates/pharmacology , Receptors, Tumor Necrosis Factor/genetics , Transcription Factor RelB/genetics , Tumor Necrosis Factors/genetics , Actins/genetics , Actins/metabolism , Alkaline Phosphatase/genetics , Alkaline Phosphatase/metabolism , Bone Morphogenetic Protein 2/genetics , Bone Morphogenetic Protein 2/metabolism , Cytokine TWEAK , Gene Expression Regulation , Humans , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Phosphates/metabolism , Primary Cell Culture , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Signal Transduction , TWEAK Receptor , Transcription Factor RelB/antagonists & inhibitors , Transcription Factor RelB/metabolism , Tumor Necrosis Factors/metabolism , Vascular Calcification/genetics , Vascular Calcification/metabolism , Vascular Calcification/pathologySubject(s)
Aspergillosis/etiology , Endocarditis, Bacterial/etiology , Heart Valve Prosthesis/adverse effects , Prosthesis-Related Infections/microbiology , Aortic Valve Stenosis/surgery , Aspergillosis/microbiology , Aspergillus flavus/isolation & purification , Cross Infection/microbiology , Endocarditis, Bacterial/microbiology , Fatal Outcome , Female , Heart Valve Prosthesis/microbiology , Humans , Middle AgedABSTRACT
No disponible
Subject(s)
Adult , Female , Humans , Syncope/etiology , Coronary Vessel Anomalies/complications , Exercise Tolerance/physiology , Risk FactorsABSTRACT
OBJECTIVE: Surgical correction for 10 supravalvular aortic stenosis since 1988. MATERIALS AND METHODS: Diagnosis was carried out by means of echocardiography and magnetic resonance. Seven patients showed features of Williams-Beuren syndrome, 5 patients showed in their genotype a delection of 7-chromosome. 5 showed membranous-localized type obstruction and the other 5 with hourglass type. The patients in the first group underwent circumferential resection of the stenosis ring followed by a diamond- shaped patch and the second group were treated with resection of the stenosing ring associated with an inverted Y- shaped patch with releasing of the coronary ostia in two of them. RESULTS: There was no hospital death. The gradient was substantially reduced from 60 +/- 8 to 5 +/- 1 mm Hg (range 0-14). The average staying was under 7 +/- 1 days. The average follow-up was 58 +/- 8 months (2-120). CONCLUSIONS: Postoperatively, all the patients were in NYHA class I-II. The residual gradient was less than 15 mmHg in the echocardiography study during the follow-up and none of them required an additional operation.
Subject(s)
Aortic Valve Stenosis/surgery , Adolescent , Child , Child, Preschool , Female , Humans , MaleABSTRACT
OBJETIVO: Corrección desde 1998 de 10 pacientes afectados de una estenosis aórtica supravalvular. MATERIAL Y MÉTODOS: El diagnóstico se realizó con ecocardiografía y resonancia magnética. Siete tenían un síndrome de Williams-Beuren, confirmándose en 5 una deleción del cromosoma 7. Cinco tenían obstrucción de tipo membranosa y otros 5 "en reloj de arena". Para el primer grupo se aplicó una resección y aortoplastia con parche en lágrima, y en el segundo grupo aortoplastia con parche en Y invertida con liberación de ostium coronario en 2 casos. RESULTADOS: No existió mortalidad en ningún grupo, reduciéndose el gradiente de 60 ñ 8 a 5 ñ 1 mmHg (rango 0-14). La estancia no fue superior a 7 ñ 1 días. El seguimiento medio fue de 58 ñ 8 meses (2-120). CONCLUSIÓN: Todos los pacientes se encuentran en grado funcional I-II de la NYHA. En los controles ecocardiográficos ningún paciente superó los 15 mmHg, no precisando reintervención (AU)