부산대학교 도서관

Introduction: Sodium-glucose co-transporter2 inhibitors (SGLT2i) showed benefit in major cardiovascular diseases characterized by low-grade inflammation. However, the role and function of SGLT2 in the heart remain unclear.Hypothesis: This study evaluated whether SGLT1/2 are expressed in the heart of patients with cardiac diseases, and determined the role of low-grade inflammation and the functional consequences.Methods: Human left ventricle (LV) biopsies were collected from 17 patients with aortic and mitral valves stenosis or hypertrophic cardiomyopathy at Strasbourg Hospital. Cultured endothelial cells (EC) were from pig coronary arteries. Expression levels were assessed by RT-qPCR, Western blot analysis and immunofluorescence staining, and the level of oxidative stress and nitric oxide (NO) using fluorescent probes.Results: SGLT1/2 protein levels were observed in the LV of cardiac patients and correlated p-p65 NFκB levels. SGLT2, VCAM-1 and TNF-α staining was observed in the endothelium of coronary microvessels and, to some extent, cardiomyocytes. TNF-α upregulated SGLT1 and 2, VCAM-1, AT1R and ACE expression and decreased that of eNOS and the bradykinin-stimulated NO formation in EC. The stimulatory effect of TNF-α was inhibited by an NF-kB inhibitor and SGLT2 siRNA but not by SGLT1 siRNA. Oxidative stress in LV sections and TNF-α-treated EC was inhibited by VAS-2870 (NADPH oxidase inhibitor), losartan (AT1R antagonist) and empagliflozin (SGLT2i), and in LV by infliximab (TNF-α receptor inhibitor).Conclusions: The findings indicate that SGLT2 is expressed in the LV of cardiac patients in the coronary endothelium and cardiomyocytes, and associated with their low-grade inflammatory status. Moreover, TNF-α upregulated the AT1R/NAPDH oxidase/SGLT2 crosstalk to sustain oxidative stress promoting endothelial dysfunction. Thus, SGLT2 appears as an interesting target to protect the coronary microcirculation.