LARS MAEGDFESSEL GROUP
Non-coding RNAs in vascular biology and medicine
Lars Maegdefessel’s Molecular Vascular Medicine group at the Center for Molecular Medicine is focused on the therapeutic and biomarker potential of non-coding RNAs in vascular disease and its underlying (patho-)mechanisms, such as atherosclerosis, aneurysm formation, inflammation, and thrombosis. His research team utilizes unique human biobank material and various pre-clinical experimental models to unravel novel treatment and detection methods on a molecular basis to combat the burden of cardiovascular diseases.
Major research focus
Tremendous efforts have been initiated to elucidate the molecular and pathophysiological characteristics of cardiovascular disease (CVD), which has developed into the most prominent factor of morbidity and mortality in our aging society. Despite these efforts to reduce the burden of CVD, the identification of the complex genetic and epigenetic regulatory circuit, as well as sufficient steering and intervention, remains a great challenge in basic cardiovascular research and everyday clinical practice. The traditional method of drug design and biomarker discovery, involving enzymes, cell surface receptors, and other proteins, has not really impacted the treatment and detection of CVD to a greater extent in the recent past, which is mainly due to the sensitive nature of the targeted system.
In this dismaying scenario, the discovery of an entirely new method of regulation and recognition by non-coding RNAs (e.g., microRNAs, lncRNAs) and their validation as markers and modulators of pathological conditions, provides new hope for innovative therapy and disease recognition approaches. The Molecular Vascular Medicine lab at Karolinska utilizes unique human biobank material (tissue and plasma) of different CVDs. Most recently the group is exploring the role of microRNAs and lncRNAs in stable and unstable atherosclerotic plaques (from patients with symptomatic and asymptomatic carotid stenosis), aortic aneurysms (thoracic and abdominal), peripheral vascular occlusive disease (PVOD), in-stent restenosis (ISR), as well as transplantation and radiation vasculopathy. Candidate ncRNAs and their putative gene (mRNA) targets and proteins are profiled and detected through different transcriptomic (RNA sequencing, microarrays), proteomic, epigenomic and genetic analyses applications.
Discoveries from human profiling studies are extensively investigated in pre-clinical models of CVD, allowing the lab to better understand the physiological and pathological function and dysfunction of ncRNA modulation. In vitro studies are deployed for in-depth mechanistic studies in disease-relevant cell types and conditions.
Collaborations and Funding
Several in-house collaborators exist, including Professor Per Eriksson and Docent Joy Roy (aneurysm disease), Professor Ulf Hedin (atherosclerotic plaque vulnerability), Professor Göran Hansson (experimental atherosclerosis research), Professor Thomas Renné (thrombosis, hemostasis and edema formation), Dr. Martin Halle (radiation vasculopathy) and Professor John Pernow (endothelial dysfunction).
External collaborations are carried out with Profs. Philip S. Tsao, Nicholas J. Leeper and Thomas Quertermous (all Stanford University, USA), Prof. Sonja Schrepfer (University Heart Center Hamburg, Germany), Dr. Jordan Miller (Mayo Clinic, USA), Prof. Kathryn Moore (New York University, USA), and Dr. Katey Rayner (Ottawa Heart Institute).
Investigations in Lars Maegdefessel’s lab are currently supported by the European Research Council (ERC StG NORVAS), the Swedish Heart-Lung Foundation, the Ragnar Söderberg Foundation, the Swedish Research Council (Vetenkapsrådet), the Cardiovascular Program (CVP) at Karolinska Institute (KI), the KI Foundation, and CERIC (Center of Excellence for Research in Inflammatory and Cardiovascular Diseases).
Awards and achievements
Prince Daniel Research Award 2014
Eken S, Jin H, Chernogubova E, Li Y, Simon N, Sun C, et al. MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions. Circ. Res. 2017 Feb;120(4):633-644.
Hartmann D, Fiedler J, Sonnenschein K, Just A, Pfanne A, Zimmer K, et al. MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. Circulation. 2016 Dec;134(24):1973-1990.
Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, John D, Lunella F, et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat. Med. 2016 Oct;22(10):1140-1150.
Kojima Y, Volkmer J, McKenna K, Civelek M, Lusis A, Miller C, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016 Aug 4;536(7614):86-90.
Wang D, Deuse T, Stubbendorff M, Chernogubova E, Erben R, Eken S, et al. Local MicroRNA Modulation Using a Novel Anti-miR-21-Eluting Stent Effectively Prevents Experimental In-Stent Restenosis. Arterioscler. Thromb. Vasc. Biol. 2015 Sep;35(9):1945-53.
Maegdefessel L, Dalman R, Tsao P. Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations. Annu. Rev. Med. 2014;65:49-62.
Maegdefessel L, Spin J, Raaz U, Eken S, Toh R, Azuma J, et al. miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat Commun. 2014 Oct 31;5:5214.
Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, et al. Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature. 2014 May;509(7502):641-4.
Maegdefessel L. The emerging role of microRNAs in cardiovascular disease. J. Intern. Med. 2014 Dec;276(6):633-44.
Maegdefessel L, Azuma J, Toh R, Deng A, Merk D, Raiesdana A, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med 2012 Feb;4(122):122ra22.
Maegdefessel L, Azuma J, Toh R, Merk D, Deng A, Chin J, et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J. Clin. Invest. 2012 Feb;122(2):497-506.