Deficiency of filamin A in endothelial cells impairs left ventricular remodelling after myocardial infarction

被引：15

作者：

Bandaru, Sashidar ^{[1
]}

Gronros, Julia ^{[2
]}

Redfors, Bjorn ^{[3
,4
]}

Cil, Caglar ^{[1
]}

Pazooki, David ^{[5
]}

Salimi, Reza ^{[1
]}

Larsson, Erik ^{[1
]}

Zhou, Alex-Xianghua ^{[3
]}

Omerovic, Elmir ^{[3
,4
]}

Akyurek, Levent M. ^{[1
,6
]}

机构：

[1] Univ Gothenburg, Inst Biomed, Dept Med Biochem & Cell Biol, SE-40530 Gothenburg, Sweden

[2] AstraZeneca, Molndal, Sweden

[3] Univ Gothenburg, Cardiovasc & Metab Res Ctr, SE-40530 Gothenburg, Sweden

[4] Sahlgrenska Acad Hosp, Dept Cardiol, Gothenburg, Sweden

[5] Sahlgrenska Acad Hosp, Dept Surg, Gothenburg, Sweden

[6] Sahlgrenska Acad Hosp, Dept Clin Pathol & Genet, Gothenburg, Sweden

来源：

CARDIOVASCULAR RESEARCH | 2015年 / 105卷 / 02期

关键词：

Actin-binding protein; Angiogenesis; Cell migration; Heart; CARDIAC VALVULAR DYSTROPHY; HYPOXIA; GROWTH; ANGIOGENESIS; PROTEIN; GENE; MICE; MORPHOGENESIS; MUTATIONS;

D O I：

10.1093/cvr/cvu226

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of FLNA after myocardial infarction (MI) has not been explored. The main purpose of this study was to determine the impact of endothelial deletion of FLNA on post-MI remodelling of the left ventricle (LV). Methods and results We found that FLNA is expressed in human and mouse endothelial cells (ECs) during MI. To determine the biological significance of endothelial expression of FLNA, we used mice that are deficient for endothelial FLNA by cross-breeding adult mice expressing floxed Flna (Flna(o/fl)) with mice expressing Cre under the vascular endothelial-specific cadherin promoter (VECadCre+). Male Flna(o/fl) and Flna(o/fl)/VECadCre+ mice were subjected to permanent coronary artery ligation to induce MI. Flna(o/fl)/VECadCre+ mice that were deficient for endothelial FLNA exhibited larger and thinner LV with impaired cardiac function as well as elevated plasma levels of NT-proBNP and decreased secretion of VEGF-A. The number of capillary structures within the infarcted areas was reduced in Flna(o/fl)/VECadCre+ hearts. ECs silenced for Flna mRNA expression exhibited impaired tubular formation and migration, secreted less VEGF-A, and produced lower levels of phosphorylated AKT and ERK1/2 as well as active RAC1. Conclusion Deletion of FLNA in ECs aggravated MI-induced LV dysfunction and cardiac failure as a result of defective endothelial response and increased scar formation by impaired endothelial function and signalling.

引用

页码：151 / 159

页数：9

共 18 条

[1] Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets [J].

Berardi, S. ;

Caivano, A. ;

Ria, R. ;

Nico, B. ;

Savino, R. ;

Terracciano, R. ;

De Tullio, G. ;

Ferrucci, A. ;

De Luisi, A. ;

Moschetta, M. ;

Mangialardi, G. ;

Catacchio, I. ;

Basile, A. ;

Guarini, A. ;

Zito, A. ;

Ditonno, P. ;

Musto, P. ;

Dammacco, F. ;

Ribatti, D. ;

Vacca, A. .

ONCOGENE, 2012, 31 (18) :2258-2269

[2] Myocardial ischemia and infarction: growth of ideas [J].

Bing, RJ .

CARDIOVASCULAR RESEARCH, 2001, 51 (01) :13-20

[3] Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway [J].

Deininger, MH ;

Wybranietz, WA ;

Graepler, FTC ;

Lauer, UM ;

Meyermann, R ;

Schluesener, HJ .

FASEB JOURNAL, 2003, 17 (10) :1267-1276

[4] Filamin B Plays a Key Role in Vascular Endothelial Growth Factor-induced Endothelial Cell Motility through Its Interaction with Rac-1 and Vav-2 [J].

del Valle-Perez, Beatriz ;

Gabriela Martinez, Vanesa ;

Lacasa-Salavert, Cristina ;

Figueras, Agnes ;

Shapiro, Sandor S. ;

Takafuta, Toshiro ;

Casanovas, Oriol ;

Capella, Gabriel ;

Ventura, Francesc ;

Vinals, Francesc .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (14) :10748-10760

[5] Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis [J].

Feng, Yuanyi ;

Chen, Ming Hui ;

Moskowitz, Ivan P. ;

Mendonza, Ashley M. ;

Vidali, Luis ;

Nakamura, Fumihiko ;

Kwiatkowski, David J. ;

Walsh, Christopher A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (52) :19836-19841

[6] Elevated Vascular Endothelial Growth Factor Receptor-2 Abundance Contributes to Increased Angiogenesis in Vascular Endothelial Growth Factor Receptor-1-Deficient Mice [J].

Ho, Vivienne C. ;

Duan, Li-Juan ;

Cronin, Chunxia ;

Liang, Bruce T. ;

Fong, Guo-Hua .

CIRCULATION, 2012, 126 (06) :741-+

[7] Hypoxia-Inducible Factor-1 in Arterial Disease: A Putative Therapeutic Target [J].

Kasivisvanathan, Veeru ;

Shalhoub, Joseph ;

Lim, Chung S. ;

Shepherd, Amanda C. ;

Thapar, Ankur ;

Davies, Alun H. .

CURRENT VASCULAR PHARMACOLOGY, 2011, 9 (03) :333-349

[8] Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy [J].

Kyndt, Florence ;

Gueffet, Jean-Pierre ;

Probst, Vincent ;

Jaafar, Philippe ;

Legendre, Antoine ;

Le Bouffant, Francoise ;

Toquet, Claire ;

Roy, Estelle ;

McGregor, Lesley ;

Lynch, Sally Ann ;

Newbury-Ecob, Ruth ;

Tran, Vinh ;

Young, Ian ;

Trochu, Jean-Noel ;

Le Marec, Herve ;

Schott, Jean-Jacques .

CIRCULATION, 2007, 115 (01) :40-49

[9] Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice [J].

Nallapalli, Rajesh K. ;

Ibrahim, Mohamed X. ;

Zhou, Alex X. ;

Bandaru, Sashidar ;

Sunkara, Sai Naresh ;

Redfors, Bjorn ;

Pazooki, David ;

Zhang, Yin ;

Boren, Jan ;

Cao, Yihai ;

Bergo, Martin O. ;

Akyurek, Levent M. .

MOLECULAR CANCER, 2012, 11

[10] Expression of the Familial Cardiac Valvular Dystrophy Gene, Filamin-A, During Heart Morphogenesis [J].

Norris, R. A. ;

Moreno-Rodriguez, R. ;

Wessels, A. ;

Merot, J. ;

Bruneval, P. ;

Chester, A. H. ;

Yacoub, M. H. ;

Hagege, A. ;

Slaugenhaupt, S. A. ;

Aikawa, E. ;

Schott, J. J. ;

Lardeux, A. ;

Harris, B. S. ;

Williams, L. K. ;

Richards, A. ;

Levine, R. A. ;

Markwald, R. R. .

DEVELOPMENTAL DYNAMICS, 2010, 239 (07) :2118-2127

← 1 2 →