TY - JOUR

T1 - Studies on sporadic non-syndromic thoracic aortic aneurysms

T2 - II. Alterations of extra-cellular matrix components and focal adhesion proteins

AU - Chiarini, Anna

AU - Onorati, Francesco

AU - Marconi, Maddalena

AU - Pasquali, Alessandra

AU - Patuzzo, Cristina

AU - Malashicheva, Anna

AU - Irtyega, Olga

AU - Faggian, Giuseppe

AU - Pignatti, Pier F.

AU - Trabetti, Elisabetta

AU - Armato, Ubaldo

AU - Dal Pra, Ilaria

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. Here, we focused on morphologic and molecular changes of the extracellular matrix of the tunica media of SNSTAAs. Design: Single centre design. Methods: Surgical media samples from seven SNSTAAs and seven controls underwent quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, histology and immunohistochemistry analysis. Results: A down-regulation of Decorin mRNA with unchanged protein levels associated with a remarkable increase of collagen fibres. A reduced and distorted network of elastic fibres partnered with an attenuated expression of microfibril-associated glycoprotein1 despite the rise of MFAP2 gene-encoded mRNA levels. An increasingly proteolysed paxillin (55 kDa PXN), a focal adhesion protein, combined with an upregulated 62 kDa PXN holoprotein, without changes in amount and phosphorylation of focal adhesion kinase (pp125FAK). The upregulation of SPOCK2-encoded Testican2 proteoglycan and of ectodysplasin (EDA) protein was coupled with a down-regulation of EDA2 receptor (EDA2R). Conclusions: Several tunica media extracellular matrix-related changes favour SNSTAA development. A steady level of decorin and a microfibril-associated glycoprotein1 protein shortage cause the assembly of structurally defective collagen and elastic fibres. Up-regulation of PXN holoproteins perturbs PXN/pp125FAK interaction and focal adhesion functioning. Testican2 up-regulation suppresses the membrane-type matrix metalloproteinase inhibiting activities of other SPOCK family members thus enhancing extracellular matrix proteolysis. Finally, the altered EDA•EDA2R signalling would impact on the remodelling of SNSTAA tunica media. Altogether, our results pave the way to a deeper molecular understanding of SNSTAAs necessary to identify their early diagnostic biochemical markers.

AB - Background: Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. Here, we focused on morphologic and molecular changes of the extracellular matrix of the tunica media of SNSTAAs. Design: Single centre design. Methods: Surgical media samples from seven SNSTAAs and seven controls underwent quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, histology and immunohistochemistry analysis. Results: A down-regulation of Decorin mRNA with unchanged protein levels associated with a remarkable increase of collagen fibres. A reduced and distorted network of elastic fibres partnered with an attenuated expression of microfibril-associated glycoprotein1 despite the rise of MFAP2 gene-encoded mRNA levels. An increasingly proteolysed paxillin (55 kDa PXN), a focal adhesion protein, combined with an upregulated 62 kDa PXN holoprotein, without changes in amount and phosphorylation of focal adhesion kinase (pp125FAK). The upregulation of SPOCK2-encoded Testican2 proteoglycan and of ectodysplasin (EDA) protein was coupled with a down-regulation of EDA2 receptor (EDA2R). Conclusions: Several tunica media extracellular matrix-related changes favour SNSTAA development. A steady level of decorin and a microfibril-associated glycoprotein1 protein shortage cause the assembly of structurally defective collagen and elastic fibres. Up-regulation of PXN holoproteins perturbs PXN/pp125FAK interaction and focal adhesion functioning. Testican2 up-regulation suppresses the membrane-type matrix metalloproteinase inhibiting activities of other SPOCK family members thus enhancing extracellular matrix proteolysis. Finally, the altered EDA•EDA2R signalling would impact on the remodelling of SNSTAA tunica media. Altogether, our results pave the way to a deeper molecular understanding of SNSTAAs necessary to identify their early diagnostic biochemical markers.

KW - aortic aneurysm

KW - cell signalling

KW - extracellular matrix

KW - gene expression

KW - remodelling

KW - Thoracic aorta

KW - CELLS

KW - PAXILLIN

KW - ACTIVATION

KW - COLLAGEN

KW - RECEPTOR

KW - TESTICAN

KW - DECORIN

KW - GROWTH-FACTOR-BETA

KW - ECTODERMAL DYSPLASIA

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85046765609&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/studies-sporadic-nonsyndromic-thoracic-aortic-aneurysms-ii-alterations-extracellular-matrix-componen

U2 - 10.1177/2047487318759120

DO - 10.1177/2047487318759120

M3 - Article

AN - SCOPUS:85046765609

VL - 25

SP - 51

EP - 58

JO - European Journal of Preventive Cardiology

JF - European Journal of Preventive Cardiology

SN - 2047-4873

IS - 1_suppl

ER -