Down-regulation of Fibulin-5 is associated with aortic dilation: role of inflammation and epigenetics
Por:
Orriols, M, Varona, S, Marti-Pamies, I, Galan, M, Guadall, A, Escudero, JR, Martin-Ventura, JL, Camacho, M, Vila, L, Martinez-Gonzalez, J, Rodriguez, C
Publicada:
1 jun 2016
Resumen:
Destructive remodelling of extracellular matrix (ECM) and inflammation lead to dilation and ultimately abdominal aortic aneurysm (AAA). Fibulin-5 (FBLN5) mediates cell-ECM interactions and elastic fibre assembly and is critical for ECM remodelling. We aimed to characterize FBLN5 regulation in human AAA and analyse the underlying mechanisms.
FBLN5 expression was significantly decreased in human aneurysmatic aortas compared with healthy vessels. Local FBLN5 knockdown promoted aortic dilation and enhanced vascular expression of inflammatory markers in Ang II-infused C57BL/6J mice. Inflammatory stimuli down-regulated FBLN5 expression and transcriptional activity in human aortic vascular smooth muscle cells (VSMC). Further, aortic FBLN5 expression was reduced in LPS-challenged mice. A SOX response element was critical for FBLN5 promoter activity. The SOX9 expression pattern in human AAA parallels that of FBLN5, and like FBLN5, it was reduced in TNF alpha-stimulated VSMC. Interestingly, SOX9 over-expression prevented the cytokine-mediated reduction of FBLN5 expression and transcription. The inhibition of Class I histone deacetylases (HDACs) by MS-275 or gene silencing attenuated the inflammation-mediated decrease of FBLN5 expression in VSMC and in the vascular wall. Consistently, HDAC inhibition counteracted the reduction of SOX9 expression induced by inflammatory stimuli and prevented the TNF alpha-mediated decrease in the binding of SOX9 to FBLN5 promoter normalizing FBLN5 expression.
We evidence the deregulation of FBLN5 in human AAA and identify a SOX9/HDAC-dependent mechanism involved in the down-regulation of FBLN5 by inflammation. HDAC inhibitors or pharmacological approaches that aimed to preserve FBLN5 could be useful to prevent the disorganization of ECM induced by inflammation in AAA.
Filiaciones:
Orriols, M:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Varona, S:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Marti-Pamies, I:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Galan, M:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Guadall, A:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Escudero, JR:
Lab Angiol Biol Vasc & Inflamac, Barcelona, Spain
Serv Cirugia Vasc, Barcelona, Spain
Martin-Ventura, JL:
IIS Fdn Jimenez Diaz, Madrid, Spain
Camacho, M:
Lab Angiol Biol Vasc & Inflamac, Barcelona, Spain
Serv Cirugia Vasc, Barcelona, Spain
Vila, L:
Lab Angiol Biol Vasc & Inflamac, Barcelona, Spain
Serv Cirugia Vasc, Barcelona, Spain
Martinez-Gonzalez, J:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
Rodriguez, C:
Hosp Santa Creu & Sant Pau, Ctr Invest Cardiovasc CSIC ICCC, IIB St Pau, Pabellon 11,Avda St Antoni Maria Claret 167, Barcelona 08025, Spain
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