Upregulation of SGLT1 and 2 promotes oxidative stress in right atrial appendages of patients with low-grade inflammatory responses: potential role in atrial fibrillation

Abstract Introduction Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with increased morbidity and mortality. Inflammatory infiltrates have been observed in atrial tissues from AF patients suggesting that low-grade inflammation contributes to pro-fibrotic, pro-remodeling pro-senescence responses of tissue favoring AF. Although sodium glucose co-transporter2 inhibitors (SGLT2i) shown beneficial effects heart failure, expression role SGLT2 remain unclear. Purpose This study examined SGLT1 2 right appendages (RAA) patients, and, if so, determine underling mechanism their functional role. Methods RAA were harvested undergoing coronary artery bypass surgery or aortic valve replacement at University Hospital Strasbourg. Patients comorbidities such as malignancies chronic inflammatory diseases excluded. The level markers was assessed using RT-qPCR, Western blot analysis, immunofluorescence staining, reactive oxygen species dihydroethidium staining. Results Analysis samples evidenced up-to a 4-fold difference NOS3 mRNA level. Those low levels showed high ICAM1, F3, MMP9, TGF-β1, TP53, CDKN1A, CDKN2A, SLCA1, SLCA2, IL1B, IL6, TNF-a CD68 whereas contrary those mRNA. SGLT1/2 negatively correlated eNOS positively IL-1, IL-6, TNF- α, CD68, senescence marker p53. analysis indicated expressing protein ICAM-1, VCAM-1, TF, MMP-2, TGF-b, SGLT1, SGLT2, p-p65, p53, p21 p16 proteins protein. Immunofluorescence staining SGLT1/SGLT2 signals colocalized CD31, an endothelial cell marker, RAA, TNF-α. Samples displayed higher oxidative stress inhibited by antioxidant NAC (N-acetylcysteine), VAS-2870 (NADPH oxidase inhibitor), perindoprilat (ACE losartan (AT1R antagonist), empagliflozin (selective sotagliflozin (dual inhibitor) infliximab (TNF-α receptor neutralizing antibody). Conclusion findings indicate are showing pro-inflammatory, pro-senescent, pro-fibrotic responses. They further sensitive either local angiotensin system, TNF-alpha SGLT2. Thus, inhibition appears be interesting approach reduce stimulatory pro-oxidant signal atrium related inflammation. Funding Acknowledgement Type funding sources: Private company. Main source(s): Boehringer Ingelheim Pharma GmbH & Co. KG