Team Per Eriksson

Transatlantic Networks of Excellence in Cardiovascular and Neurovascular Research -- MIBAVA -- Mechanistic interrogation of bicuspid aortic valve aortopathy

Research focus

Molecular pathology of aortic aneurysm, allele-specific gene expression

Introduction

The long-term interest of the Eriksson team is to investigate the underlying molecular mechanism of aortic aneurysm development. Aortic aneurysms are characterized by a degradation of the extra cellular matrix leading to a dilatation and eventually rupture of the vessel wall. The disease involves loss of elastin and remodeling of collagen, which are load bearing components of the vessel wall.

Major research focus

One of our main goals is to understand the underlying mechanism of the common aortopathy associated with a bicuspid aortic valve (BAV).  BAV is the most common congenital disorder of the aortic valve and is present in 1-2 % of the population. The presence of a BAV predisposes for progressive dilatation of the ascending aorta and thereby constitutes an increased risk of aortic aneurysm that may eventually lead to fatal rupture or dissection of the aorta. The prevalence of aortic dilatation in patients with BAV has been estimated to be as high as 50-70%. As yet, the pathophysiologic basis for the increased risk of aortic complications associated with BAV is not known.

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 . Recently, an increasing number of researchers agree that both factors may contribute to BAV related cardiac complications.

Our research team’s goal is to understand how different signaling pathways interact to bring about the similarities and differences in molecular events of aneurysm formation in patients with BAV and patients with a normal tricuspid aortic valve (TAV). Besides inherited properties, we also 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. Importantly, we have collected large and well characterized unique biobank, including tissue biopsies from dilated and non-dilated aorta in addition to DNA, plasma and serum samples. 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

Affiliated to the team is Lasse Folkersen, PhD, Technical University of Denmark.

 

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 Docent Rebecka Hultgren at the Vascular Surgery group, Karolinska University Hospital Solna (http://ki.se/en/mmk/star-stockholm-aneurysm-research-group).  

We are member of Leducq transatlantic network on BAV disease MIBAVA. The studies are supported by the Swedish Research Council and the Swedish Heart-Lung Foundation.

Team members

Per Eriksson PhD, Professor, Group Leader

Shohreh Maleki PhD, Researcher

Karin Lundströmer Laboratory assistant  

Jesper Gådin PhD Student

Hanna Björck PhD, Assistant Professor

Lei Du PhD, Post Doctoral Fellow

Anirban Bhattachariya, PhD, Post Doctoral Fellow

Recent key publications

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.
Jones G, Tromp G, Kuivaniemi H, Gretarsdottir S, Baas A, 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 F, et al
Nat. Med. 2016 Oct;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 R, Du L, et al
Sci Rep 2016 Oct;6():35712

NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis.
Paramel Varghese G, Folkersen L, Strawbridge R, Halvorsen B, Yndestad A, Ranheim T, et al
J Am Heart Assoc 2016 May;5(5):

Elevated Adiponectin Levels Suppress Perivascular and Aortic Inflammation and Prevent AngII-induced Advanced Abdominal Aortic Aneurysms.
Wågsäter D, Vorkapic E, van Stijn C, Kim J, Lusis A, 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 J, Khan S, Björck H, 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 J, Raaz U, Eken S, Toh R, Azuma J, et al
Nat Commun 2014 Oct;5():5214

Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve.
Maleki S, Björck H, Folkersen L, Nilsson R, Renner J, Caidahl K, et al
J. Mol. Med. 2013 Jan;91(1):129-39

Interleukin-6 receptor pathways in abdominal aortic aneurysm.
Harrison S, Smith A, Jones G, Swerdlow D, Rampuri R, Bown M, 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 R, Lehtiö J, et al
Mol. Cell Proteomics 2013 Feb;12(2):407-25

Impaired collagen biosynthesis and cross-linking in aorta of patients with bicuspid aortic valve.
Wågsäter D, Paloschi V, Hanemaaijer R, Hultenby K, Bank R, Franco-Cereceda A, et al
J Am Heart Assoc 2013 Feb;2(1):e000034

Aneurysm Development in Patients With Bicuspid Aortic Valve (BAV): Possible Connection to Repair Deficiency?
Maleki S, Björck H, Paloschi V, Kjellqvist S, Folkersen L, Jackson V, et al
Aorta (Stamford) 2013 Jun;1(1):13-22

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
Holmes M, Simon T, Exeter H, Folkersen L, Asselbergs F, Guardiola M, et al
J. Am. Coll. Cardiol. 2013 Nov;62(21):1966-1976

A variant in LDLR is associated with abdominal aortic aneurysm.
Bradley D, Hughes A, Badger S, Jones G, Harrison S, Wright B, et al
Circ Cardiovasc Genet 2013 Oct;6(5):498-504