Niels Riksen - Selected Publications#
1. El Messaoudi S, Nederlof R, Zuurbiers CJ, van Swieten HA, Picckers P, Noyez L, Dieker HJ, Coenen MJ, Donders RT, Vos A, Rongen GA, Riksen NP. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomized controlled trial. Lancet Diab Endocrinol 2015; 3: 615-623. (Impact factor 44.5)
A commentary (van der Horst, Lancet Diab Endocrinol 2015;3(8);581-582) acknowledged the rigorous design and conclusion that metformin does not directly protect the heart. Based on ref. 1, I was invited to contribute to a position paper on Heart Failure and Diabetes of the European Society of Cardiology, in which our study was mentioned (doi: 10.1093/eurheartj/ehy596).
2. Bekkering S, Quintin J, Joosten LA, van der Meer JWM, Netea MG, Riksen NP. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol 2014;34:1731-8. (Impact factor 8.7; Highly cited paper Web of Science; 380 citations; 38/year)
3. van der Valk FM, Bekkering S, Kroon J, Yeang C, van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LAB, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ESG. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 2016;134:611-24. (Impact factor 37.8; Highly cited paper Web of Science; 302 citations)
4. van der Heijden, CDCC, Groh, L, Keating ST, Kaffa C, Noz MP, Kersten S, Hoischen A, Joosten LAB, Timmers HJLM, Netea MG, Riksen NP. Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ Res 2020;127(2):269-283. (Impact factor 20.1)
In ref. 2 we discovered that brief exposure of human monocytes to endogenous atherogenic lipid particles induces a long-lasting pro-inflammatory macrophage phenotype, i.e., induces trained immunity. We proposed for the first time that trained immunity contributes to atherogenesis. The novelty of this finding is illustrated by the high citations number (Highly cited paper Web of Science; 380 citations). We subsequently showed that also other pro-atherogenic molecules induce trained immunity, including lipoprotein (a) (ref. 3, Highly cited paper Web of Science; 302 citations; I was responsible for the in-vitro studies), and catecholamines (ref. 4, 56 citations/3 years).
5. Bekkering S*, Arts RJW*, Novakovic B, Kourtzelis I, Popa CD, ter Horst R, van Tuijl J, Simon A, van de Veerdonk FL, Chavakis T, Joosten LAB, Van der Meer JWM, Stunnenberg H, Riksen NP†, Netea MG†. †Shared senior authorship. Metabolic induction of trained immunity involves mevalonate pathway. Cell. 2018;172(1-2):135-146. (Impact factor 64.5; Highly cited paper Web of Science; 397 citations).
6. Keating ST, Groh L, van der Heijden CDCC, Rodriguez H, dos Santos J, Fanucchi S, Okabe J, KN H, van Puffelen JH, Helder L, Noz MP, Matzaraki V, Li Y, de Bree LCJ, Koeken VACM, Moorlag SJCFM, Mourits VP, Domínguez-Andrés J, Oosting M, Mhlanga M, El-Osta A, Joosten LAB, Netea MG, Riksen NP. The Set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by beta-glucan. Cell Rep 2020;31(3):107548. (Impact factor 8.8)
Together with my group, I subsequently unraveled key epigenetic and metabolic mechanisms mediating trained immunity. We identified the mevalonate synthesis pathway as such a pivotal mechanism (ref 5, Highly cited paper Web of Science; 397 citations). We further discovered that the epigenetic enzyme Set7 is indispensable for trained immunity, using cell-cultures and in vivo murine models. These experiments for the first time identified a key enzymatic target for pharmacological modulation of trained immunity (ref 6, 55 citations/3 years), which resulted in a collaborative project with the Belgian Centre for Drug Design and Discovery CD3.
7. Bekkering S, van den Munckhof I, Nielen T, Lamfers E, Dinarello C, Rutten J, de Graaf J, Joosten LAB, Netea MG, Gomes MER, Riksen NP. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis 2016;254:228-236. (Impact factor 5.5; 136 citations; 17/year)
8. Bekkering S, Stiekema LCA, Bernelot Moens S, Verweij SL, Pranga K, Versloot M, Roeters van Lennep JE, Stunnenberg H, de Winther M, Stroes ESG, Joosten LAB, Netea MG, Riksen NP. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab 2019;30(1):1-2. (Impact factor 29.0)
9. Noz MP, Bekkering S, Groh L, Nielen TMJ, Lamfers EJP, Schlitzer A, El Messaoudi S, van Royen N, Huys HJPG, Prijers FWMB, Smeets EMM, Aarntzen EHJG, Zhang N, Li Y, Bremmers MEJ, van der Velden
WJFM, Dolstra H, Loosten LAB, Gomes MER, Netea MG, Riksen NP. Reprogramming of bone marrow myeloid progenitors in patients with severe coronary artery disease. eLife 2020;9:e60939. (Impact factor 7.7)
Ref 7-8-9 illustrate how my group subsequently translated the in vitro identification and mechanisms of trained immunity to patients with CVD or CVD risk factors. Ref 7 describes how we identified critical metabolic and epigenetic markers of trained immunity (i.e. glycolytic activation and specific histone markers) in isolated monocytes from patients with established coronary artery disease (136 citations, 17/yr). We also showed this in patients with familial hypercholesterolemia (Ref 8, 76 citations, 15/yr). A very exciting and novel recent breakthrough in the cardiovascular field was our demonstration that in patients with coronary artery disease, the bone marrow hematopoietic progenitor cells also show functional, metabolic, and transcriptional reprogramming (Ref 9). The importance of the research line described above for the broad scientific audience is illustrated by a recent Nature Outlook paper by Amanda Keener on trained immunity in CVD, which extensively discusses Refs 2, 7, 8, and 9, and includes an interview with me and my former PhD student Siroon Bekkering (Keener AB, The ghost of immunity past. Nature 2021;594;S10-S11).
10. Riksen NP, Bekkering S, Mulder WJM, Netea MG. Trained immunity in atherosclerotic cardiovascular disease. Nat Rev Cardiol 2023 Jun 15. doi: 10.1038/s41569-023-00894-y. Online ahead of print. (Impact factor 49.6)
Ref. 10 was the result of a personal invitation to write a review in the highest-ranked cardiovascular journal (IF 49.6) about my work on trained immunity in cardiovascular diseases.
