Team Hanna Björck

Research focus

Molecular pathology of aortic aneurysm, allele-specific gene expression.

Introduction

The long-term interest of the team is to investigate the underlying molecular mechanism of aortic aneurysm development. Aortic aneurysm is a silent disease and the first manifestation is often aortic dissection or aortic rupture, both lethal conditions unless surgery is performed acutely. Our studies aim at gaining insights regarding the clinical course and predictors of outcome in aortic aneurysm, to identify biomarkers for the disease and to elucidate the ethiologies and pathogenic mechanisms.

Major research focus

We have previously shown that being born with a bicuspid (BAV) instead of the normal tricuspid (TAV) aortic valve is a major risk factor for developing aneurysm in the ascending aorta. BAV is, by far, the most common congenital heart disorder, and is present in 1-2% of the population.

Currently, two major hypotheses have been proposed to explain the more fragile aorta in BAV patients. The first is that a developmental abnormality or a genetic predisposition in BAV results in structural weakness of the aorta, which renders it more susceptible to aortic complications. The second or ‘’hemodynamic’’ theory argues that the chronic exposure of ascending aortic wall to higher blood flow velocities and eccentric flow jets due to the geometry of a BAV lead to a higher propensity of the BAV aorta to aorthopathy.

A unique clinical cohort is the basis for our research. Our biobank includes at present >1800 patients undergoing valve replacement and/or repair of the ascending aorta. Today our cohort is one of the largest and most comprehensive in the world. The extensive biobank consists of DNA, plasma, serum, and vascular tissue biopsies from all patients. Uniquely, we have collected biopsies from multiple tissues from the same individual of the first 600 patients (ascending aorta, internal thoracic artery, heart, and liver). Furthermore, smooth muscle cells and endothelial cells from ascending aortas of BAV and TAV patients have been isolated. Besides inherited properties, we study the possible dysregulation of biological pathways due to abnormal hemodynamic stress, which may contribute and/or lay the foundation for more fragility in BAV aorta. In order to do so, we integrate the core molecular biology with genomic, genetic and bioinformatics analysis. Candidate genes and pathways are initially identified by transcriptomics, proteomics, epigenomics and genetic analyses. Functional evaluations are performed using cell culture and in vitro analyses. RNA sequencing is used to study allele-specific gene expression.

Collaborations

The study on BAV associated aortopathy is a close collaboration with the group of Professor Anders Franco-Cereceda at the Cardiothoracic Surgery Unit at the Karolinska University Hospital Solna. Studies on abdominal aortic aneurysm are in collaborations with Docent Joy Roy and Professor Rebecka Hultgren at the Vascular Surgery group, Karolinska University Hospital Solna (http://ki.se/en/mmk/star-stockholm-aneurysm-research-group). We have been members of Leducq transatlantic network on BAV disease MIBAVA and the EU-financed network, FAD, Fighting Aneurysmal Disease. The studies are supported by the Swedish Research Council, the Swedish Heart-Lung Foundation and the Stockholm County Council.

Affiliated to the team are Lasse Folkersen, PhD, Sankt Hans Hospital Roskilde, Denmark, and Maria Sabater Lleal, PhD, Senior Researcher, Research Institute Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Team members

Hanna Björck PhD, Assistant Professor, Team leader

Per Eriksson PhD, Professor

Karin Lång Laboratory Assistant

Otto Bergman PhD, Bioinformatician

David Freiholtz MD, PhD student

Carl Granath MD, PhD student

Anders Hamsten MD, PhD, Professor, Associated

Bamba Gaye PhD, Associated

Maxim Vignac Associated

Recent key publications

High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways.
Åkerborg Ö, Spalinskas R, Pradhananga S, Anil A, Höjer P, Poujade FA, et al
Circ Genom Precis Med 2019 Mar;12(3):e002353

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.
Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, et al
Nat. Genet. 2019 01;51(1):42-50

The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.
Maleki S, Cottrill KA, Poujade FA, Bhattachariya A, Bergman O, Gådin JR, et al
J. Intern. Med. 2019 Jan;285(1):102-114

Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve.
Björck HM, Du L, Pulignani S, Paloschi V, Lundströmer K, Kostina AS, et al
Sci Rep 2018 Feb;8(1):2777

Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm.
Di Gennaro A, Araújo AC, Busch A, Jin H, Wågsäter D, Vorkapic E, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 02;115(8):1907-1912

Neutrophil Elastase-Derived Fibrin Degradation Products Indicate Presence of Abdominal Aortic Aneurysms and Correlate with Intraluminal Thrombus Volume.
Lindquist Liljeqvist M, Silveira A, Hultgren R, Frebelius S, Lengquist M, Engström J, et al
Thromb. Haemost. 2018 02;118(2):329-339

Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
Yang B, Zhou W, Jiao J, Nielsen JB, Mathis MR, Heydarpour M, et al
Nat Commun 2017 05;8():15481

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.
Jones GT, Tromp G, Kuivaniemi H, Gretarsdottir S, Baas AF, Giusti B, et al
Circ. Res. 2017 Jan;120(2):341-353

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.
Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella FF, et al
Nat. Med. 2016 10;22(10):1140-1150

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves.
Maleki S, Kjellqvist S, Paloschi V, Magné J, Branca RM, Du L, et al
Sci Rep 2016 10;6():35712

Elevated Adiponectin Levels Suppress Perivascular and Aortic Inflammation and Prevent AngII-induced Advanced Abdominal Aortic Aneurysms.
Wågsäter D, Vorkapic E, van Stijn CM, Kim J, Lusis AJ, Eriksson P, et al
Sci Rep 2016 Sep;6():31414

Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-β activation.
Paloschi V, Gådin JR, Khan S, Björck HM, Du L, Maleki S, et al
Arterioscler. Thromb. Vasc. Biol. 2015 Apr;35(4):973-80

TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Jun;111(24):8913-8

miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development.
Maegdefessel L, Spin JM, Raaz U, Eken SM, Toh R, Azuma J, et al
Nat Commun 2014 Oct;5():5214

Interleukin-6 receptor pathways in abdominal aortic aneurysm.
Harrison SC, Smith AJ, Jones GT, Swerdlow DI, Rampuri R, Bown MJ, et al
Eur. Heart J. 2013 Dec;34(48):3707-16

A combined proteomic and transcriptomic approach shows diverging molecular mechanisms in thoracic aortic aneurysm development in patients with tricuspid- and bicuspid aortic valve.
Kjellqvist S, Maleki S, Olsson T, Chwastyniak M, Branca RM, Lehtiö J, et al
Mol. Cell Proteomics 2013 Feb;12(2):407-25