N-glikozilacija ukupnih plazmatskih proteina i imunoglobulina G u fibrilaciji atriija

doctoral thesis

• Title (english): N-glycosylation of total plasma proteins and immunoglobulin G in atrial fibrilation
• Author: Branimir Plavša
• Mentor: Gordan Lauc (mentor)
• Committee member: Toma Keser (predsjednik povjerenstva)
• Committee member: Ivan Gudelj (član povjerenstva)
• Committee member: Edvard Galić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of biochemistry and molecular biology); Zagreb
• Defense date and country: 2024-02-09, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Fibrilacija atrija je bolest kompleksne patofiziologije čiji razvoj i perzistencija nisu uzrokovani samo nepravilnim
električnim signaliziranjem u srcu nego i razvojem promjena u srčanom mišiću koje rezultiraju supstratom
podložnim za nastanak i progresiju bolesti. Promjene poput razvoja intersticijske fibroze i akumulacije
epikardijalnog adipoznog tkiva su uzrokovane lokalnim upalnim odgovorom te također potiču nastanak istog. Nglikani ukupnih plazmatskih proteina i imunoglobulina G su dokazani biljezi različitih bolesti, pogotovo onih u
kojima je izražena upalna ili metabolička komponenta kao što su dijabetes, hipertenzija i kardiovaskularne bolesti.
Sva navedena stanja su čimbenici rizika za fibrilaciju atrija te su stoga potencijalno povezani s razvojem i
progresijom bolesti. Važna uloga N-glikozilacije proteina plazme, a posebno imunoglobulina G (IgG) u upalnom
odgovoru, kao i spomenuta povezanost s čimbenicima rizika, motiviraju istraživanje N-glikozilacije ukupnih
plazmatskih proteina i izoliranog IgG-a u fibrilaciji atrija. Kako bi ispitali potencijalne promjene, analizirali smo
N-glikome IgG-a i ukupnih plazmatskih proteina 172 pacijenta s fibrilacijom atrija i usporedili ih s N-glikomima
54 kardiološki zdravih kontrola. Pacijenti su također bili podvrgnuti zahvatu kateterske ablacije te su uzorci
prikupljeni u dvije vremenske točke, neposredno prije zahvata i nakon šest mjeseci, tijekom kojih su pacijenti
praćeni za recidiv fibrilacije atrija. Analiza N-glikozilacije provedena je koristeći visoko-protočnu metodu
temeljenu na tekućinskoj kromatografiji ultra-visoke učinkovitosti. Jedan oligomanozni glikan iz N-glikoma
ukupnih plazmatskih proteina te šest glikana IgG-a pokazali su statistički značajne promjene između zdravih
kontrola i osoba oboljelih od fibrilacije atrija. Promjene su bile izraženije u IgG-u, te su promjene vezane uz
smanjenje razine struktura s račvajućim N-acetilglukozaminom bile specifične za fibrilaciju atrija. Uz to, četiri
glikana u N-glikomu plazme, pretežito oligomanozne strukture, pokazale su značajne razlike između podskupine
pacijenata koja je doživjela recidiv fibrilacije atrija nakon zahvata te one za koje je odsustvo fibrilacije atrija bilo
stabilno unutar vremena ove studije. IgG N-glikom je također opsežno korelirao s CHA2DS2-VASc procjenom
rizika od moždanog udara, gdje je opažen pomak IgG glikoma prema porupalnom fenotipu kako se CHA2DS2-
VASc vrijednost povećava. Ovo je prvo istraživanje koje je usporedilo N-glikome proteina plazme i izoliranog
IgG-a pacijenata s fibrilacijom atrija s zdravim kontrole te ovdje opisani rezultati daju temelj za daljnje glikomske
studije fibrilacije atrija.

Abstract (english)

Atrial fibrillation is a disease with a complex pathophysiology whose onset and persistence are caused not only by
irregular electric signalling, but also the development of changes in the heart muscle itself which form the substrate
that is susceptible to disease progression. Changes such as interstitial fibrosis and the accumulation of epicardial
adipose tissue are caused by a local inflammatory response and also support further inflammation. N-glycans of
total plasma proteins and immunoglobulin G (IgG) have been shown to be biomarkers for many diseases,
especially those with pronounced inflammatory or metabolic components such as diabetes, hypertension and
cardiovascular diseases. These conditions are also risk factors for atrial fibrillation and are therefore potentially
connected to the development and progression of the atrial fibrillation. Important role of plasma protein Nglycosylation and IgG specifically in the inflammatory response, as well as the aforementioned association with
atrial fibrillation risk factors warrant the study of N-glycosylation of total plasma proteins and IgG in atrial
fibrillation. To assess potential changes in N-glycosylation we analysed IgG and total plasma protein N-glycomes
of 172 patients with atrial fibrillation and compared them to the glycomes of 54 healthy controls. Patients also
underwent catheter ablation and samples were collected in two timepoints, first immediately before the procedure,
and the second after the six-month follow-up during which time the patients were monitored for recurrence of
atrial fibrillation. N-glycosylation analysis was performed using a high-throughput ultra-high performance liquid
chromatography method. One oligomannose plasma N-glycan and six IgG N-glycans showed statistically
significant differences between patient and control groups. Changes were more extensive in IgG and the changes
specific to atrial fibrillation were the decreased levels of bisecting structures. Also, four plasma N-glycans, mainly
oligomannose structures were associated with recurrence of atrial fibrillation during the six-month period. IgG Nglycome also extensively correlated with the CHA2DS2-VASc risk score for stroke wherein a increase in risk score
was followed by a greater shift towards the proinflammatory IgG glycan profile. This was the first study that
compared patients with atrial fibrillation and healthy controls and the findings provide a basis for further glycomic
studies of atrial fibrillation.

• Keywords: N-glikozilacija; N-glikani; Fibrilacija atrija; N-glikani imunoglobulina G; N-glikani ukupnih plazmatskih proteina; UPLC
• Keywords (english): N-glycosylation; N-glycans; Atrial fibrillation; Immunoglobulin G N-glycans; Total plasma protein N-glycans; UPLC
• Language: croatian
• URN:NBN: urn:nbn:hr:163:855145
• Promotion: 2024
• Study programme: Title: Pharmceutical-biochemical sciences - doctoral study - university study; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti u području biomedicine i zdravstva (doktor/doktorica znanosti u području biomedicine i zdravstva)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-06-11 12:42:32