Ljubica Matic Group

The Translational Vascular Medicine group has been established and led since 2019 at CMM by Ljubica Matic. The group works under the umbrella of Vascular Surgery, a large unit at Karolinska built over the past 50 years between the Vascular Surgery Clinic and Vascular Surgery Research, where Ljubica Matic acts as one of the senior PIs.

Ljubica Matic is devoted to translational research on novel therapeutic and diagnostic targets for management of cardiovascular disease (CVD), specifically atherosclerosis and restenosis. Atherosclerosis is the major aetiology behind CVD, leading to high mortality due to plaque rupture, myocardial infarction and stroke. Despite decades of research, there are still no biomarkers for prediction of rupture events, nor targeted therapies to alleviate plaque burden in patients, highlighting an urgent clinical need.

Her group Translational Vascular Medicine group utilizes innovative, integrated multi-omics in silico pipelines for exploration of the Biobank of Karolinska Endarterectomy (BiKE, est. 2002, around 2000 patients) to identify smooth muscle cells targets that stand in direct causal relationship to human vascular disease, with increased translational potential. Phenotyping, challenge, and proof-of-concept interventional studies in mice vascular models, as well as in vitro studies of selected targets using primary human smooth muscle cells are also performed.

With this multi-disciplinary approach, the mission of Ljubica Matic is to create a powerful platform for extrapolation of basic research results into the various realms of clinical cardiovascular disease, leading to the accelerated developments of new drugs and biomarkers, from target discovery to patient treatment.

1. Harnessing the potential of smooth muscle cells for treatment of vascular diseases

Smooth muscle cells build the vessel wall and are normally programmed to contract and regulate blood pressure. But they also play an important role in vascular diseases, such as atherosclerotic plaque rupture that can lead to heart attacks and strokes, or in stent implantation and other surgical interventions that can cause vascular damage. But we don’t know enough about what drives these processes and how smooth muscle cells can be used to heal vascular injuries.

Our project focuses on understanding different smooth muscle cell subtypes and developing tailored treatment options based on their mechanisms. We aim to investigate how smooth muscle cell function is regulated in diseases such as atherosclerosis. We are doing this by analyzing molecules in atherosclerosis plaques from biobanks of patients who underwent vascular surgery at Karolinska University Hospital since 2003. We use advanced molecular analyses, bioinformatics and biostatistics to examine candidate molecules from these samples. The identified molecular candidates are then studied in experimental models in the research lab. We also work to validate the candidates in other international biobanks through collaborations, to asure their value as therapeutic targets or biomarkers to predict risk and make diagnostic assessments.

By understanding the mechanisms that regulate the properties of smooth muscle cells, we will be able to develop new strategies to prevent complications that can occur during stent implantation and vascular diseases such as heart attacks and strokes.

2. The function and therapeutic targeting of proprotein convertases (PCSKs) in vascular disease

By molecular profiling of human atherosclerotic plaques, we discovered in 2013 that Proprotein Convertase Subtilisin Kexin 6 (PCSK6) is one of the most enriched molecules in lesions from patients with stroke symptoms, localized to plaque smooth muscle cells and induced by growth factors and inflammation. Further investigations in PCSK6 knock-out mice, murine vascular injury models, ex vivo and in vitro studies in primary vascular tissues and cells, identified the functional link among increased PCSK6 levels, vascular remodeling via MMP2/MMP14 and smooth muscle cell activation towards proliferation/migration in disease.

Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-6, FURIN, MBTPS1, and PCSK9. These proteases have been poorly studied in vascular disease, although their role in growth factor processing and cell activation is well established in cancer. Apart from PCSK9, which is a major target for lipid lowering in patients with high LDL cholesterol, little is known about the role of other PCSKs in vascular disease. We aim to investigate in detail the expression landscape and druggability potential of the entire PCSK family for cardiovascular disease.

 We are conducting the first comprehensive exploration of PCSK-dependent mechanisms in vascular disease, particularly focusing on their role in smooth muscle cells and utilizing an integrative systems approach with deep profiling from independent human cohorts, combining early and advanced atherosclerosis, coronary artery disease, aortic aneurysm and experimental in vivo and in vitro studies. In collaborations with pharmaceutical industry, candidates with translational potential are further evaluated as biomarkers or therapeutic targets, to improve care of vascular patients.

Ljubica Matic

MSc, PhD, Assoc Professor

Principal Researcher at the Department of Molecular Medicine and Surgery

Group Leader at the Center for Molecular Medicine

Karolinska Institutet

AREAS OF EXPERTISE (KEYWORDS):

molecular medicine, vascular disease, atherosclerosis, smooth muscle cells, glomerular dysfunction, podocytes, biobanking and clinical cohorts, multi-omics

Biosketch:

I have a MSc in Molecular Biology from Belgrade University, Serbia and a PhD in Medical Biochemistry from Karolinska Institute, Sweden. In 2021 I became Associate Professor in Molecular Medicine at Karolinska Institute, where I lead a research group that focuses on identification and characterisation of novel therapeutic and diagnostic targets for management of vascular disease, in particular atherosclerosis. As a molecular biologist, I am devoted to translational research in vascular disease related to the mechanisms of smooth muscle cell trans-differentiations. I also have previous experience in molecular pathophysiology of end-stage renal disease and glomerular podocytes.

Since 2013 I serve as one of the PIs for the Biobank of Karolinska Endarterectomies (BiKE, est 2002) and have coordinated several large EU projects and partnerships with Pharma Industry. As expert reviewer I work for the EU Horizon Marie Skłodowska-Curie Actions, Danish Cardiovascular Academy, UK National Centre for the Replacement, Refinement & Reduction of Animals in Research, Polish National Research Council, Austrian National Science Fund, Swiss National Science Foundation and the Dutch Innovation Research Incentives Scheme, KI Doctoral grants committee, as well as numerous scientific journals (e.g. Nature Cardiovasc Research; JACC; American Journal of Human Genetics; FASEB; Journal of Internal Medicine; Atherosclerosis, Thrombosis and Vascular Biology; Cardiovascular Research; Atherosclerosis; Vascular Pharmacology; Molecular Therapy).

Over the years, my research presented in nearly 100 publications distinguished by grants from the Swedish Research Council, KI Consolidator program, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, etc. as well as awards such as American Heart Association Daniel Steinberg Early Career Investigator Award, Sven and Ebba Hagberg Award, American Heart Association Young Investigator Award, etc.

With respect to teaching and pedagogical duties, I develop and organise KI courses on PhD level in Vascular Cell Biology and MSc level for the KI Biomedicine Program, elective track in Circulation, Metabolism and Endocrinology.

Ljubica Matic, Assoc Prof, Group Leader Ljubica.Matic@ki.se

Eva Hurt-Camejo, PhD, Adjunct Prof Eva.Hurt-Camejo@ki.se

Hong Jin, MD, PhD, Senior Research Specialist Hong.Jin@ki.se

Melody Chemaly, PhD, postdoc Melody.Chemaly@ki.se

Glykeria Karadimou, PhD, postdoc Glykeria.Karadimou@ki.se

Katarina Wadén, DMD, MD, PhD student Katarina.Waden@ki.se

Sofija Vuckovic, MSc, PhD student Sofija.Vuckovic@ki.se

Inika Prasad, MSc student Inika.Prasad@ki.se

Alumni:

2019-2022 Nikolaos-Taxiarchis Skenteris, PhD student

2017-2022 Bianca Suur, PhD student

2015-2022 Urszula Rykaczewska, PhD student

Rykaczewska, U; Suur, BE; Röhl, S; Razuvaev, A; Lengquist, M; Sabater-Lleal, M; van der Laan, SW; Miller, CL; Wirka, RC; Kronqvist, M; Gonzalez Diez, M; Vesterlund, M; Gillgren, P; Odeberg, J; Lindeman, JH; Veglia, F; Humphries, SE; de Faire, U; Baldassarre, D; Tremoli, E; Lehtiö, J; Hansson, GK; Paulsson-Berne, G; Pasterkamp, G; Quertermous, T; Hamsten, A; Eriksson, P; Hedin, U; Matic, L. PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling. Circulation Research 126;571-585.5 (2020, JIF 23.2, featured in an editorial and journal cover page).

https://www.ncbi.nlm.nih.gov/pubmed/31893970

Kojima, Y; Volkmer, JP; McKenna, K; Civelek, M; Lusis, AJ; Miller, CL; Direnzo, D; Nanda, V; Ye, J; Connolly, AJ; Schadt, EE; Quertermous, T; Betancur, P; Maegdefessel, L; Matic, LP; Hedin, U; Weissman, IL; Leeper, NJ. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536;86-90.7614 (2016, JIF 69.5, among top 5% citations, featured in an editorial).

https://pubmed.ncbi.nlm.nih.gov/27437576/

Rykaczewska, U; Zhao, Q; Saliba-Gustafsson, P; Lengquist, M; Kronqvist, M; Bergman, O; Huang, Z; Lund, K; Waden, K; Pons Vila, Z; Caidahl, K; Skogsberg, J; Vukojevic, V; Lindeman, JHN; Roy, J; Hansson, GK; Treuter, E; Leeper, NJ; Eriksson, P; Ehrenborg, E; Razuvaev, A; Hedin, U; Matic, L. Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis. ATVB 42;659-676.5 (2022, JIF 10, featured as the best paper of the month and year).

https://pubmed.ncbi.nlm.nih.gov/35321563/

Skenteris, NT; Seime, T; Witasp, A; Karlöf, E; Wasilewski, GB; Heuschkel, MA; Jaminon, AMG; Oduor, L; Dzhanaev, R; Kronqvist, M; Lengquist, M; Peeters, FECM; Söderberg, M; Hultgren, R; Roy, J; Maegdefessel, L; Arnardottir, H; Bengtsson, E; Goncalves, I; Quertermous, T; Goettsch, C; Stenvinkel, P; Schurgers, LJ; Matic, L. Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification. Clinical and Translational Medicine 12; e682-.2 (2022, JIF 8.6).

https://pubmed.ncbi.nlm.nih.gov/35184400/

Suur, BE; Chemaly, M; Lindquist Liljeqvist, M; Djordjevic, D; Stenemo, M; Bergman, O; Karlöf, E; Lengquist, M; Odeberg, J; Hurt-Camejo, E; Eriksson, P; Ketelhuth, DFJ; Roy, J; Hedin, U; Nyberg, M; Matic, L. Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease. Frontiers in Pharmacology 13; 988561- (2022, JIF 6)

https://pubmed.ncbi.nlm.nih.gov/36188622/

Waden K, Hultgren R, Kotopouli MI, Gillgren P, Roy J, Hedin U, Matic L. Long Term Mortality in Patients Treated with Carotid Endarterectomy. European journal of vascular and endovascular surgery. 2023 Jun; 65(6):778-786. (2023, JIF 6.43)

https://pubmed.ncbi.nlm.nih.gov/36871924/

Matic, LP; Jesus Iglesias, M; Vesterlund, M; Lengquist, M; Hong, MG; Saieed, S; Sanchez-Rivera, L; Berg, M; Razuvaev, A; Kronqvist, M; Lund, K; Caidahl, K; Gillgren, P; Pontén, F; Uhlén, M; Schwenk, JM; Hansson, GK; Paulsson-Berne, G; Fagman, E; Roy, J; Hultgren, R; Bergström, G; Lehtiö, J; Odeberg, J; Hedin, U. Novel Multiomics Profiling of Human Carotid Atherosclerotic Plaques and Plasma Reveals Biliverdin Reductase B as a Marker of Intraplaque Hemorrhage. JACC. Basic to Transl Science. 3;464-480.4 (2018, JIF 9.5, featured in an editorial)

https://pubmed.ncbi.nlm.nih.gov/30175270/

Perisic, L; Hedin, E; Razuvaev, A; Lengquist, M; Osterholm, C; Folkersen, L; Gillgren, P; Paulsson-Berne, G; Ponten, F; Odeberg, J; Hedin, U. Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis. ATVB 33;2432-43.10 (2013, JIF 10)

https://pubmed.ncbi.nlm.nih.gov/23908247/

Perisic, L; Lal, M; Hulkko, J; Hultenby, K; Önfelt, B; Sun, Y; Dunér, F; Patrakka, J; Betsholtz, C; Uhlen, M; Brismar, H; Tryggvason, K; Wernerson, A; Pikkarainen, T. Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics. Kidney International 82;1071-83.10 (2012, JIF 19)

https://pubmed.ncbi.nlm.nih.gov/22832517/

 Perisic, L; Aldi, S; Sun, Y; Folkersen, L; Razuvaev, A; Roy, J; Lengquist, M; Åkesson, S; Wheelock, CE; Maegdefessel, L; Gabrielsen, A; Odeberg, J; Hansson, GK; Paulsson-Berne, G; Hedin, U. Gene expression signatures, pathways and networks in carotid atherosclerosis. Journal of Internal Medicine 279; 293-308.3 (2016, JIF 13, among top 5% cited publications)

https://pubmed.ncbi.nlm.nih.gov/26620734/