Aims: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a cardioprotective effect in heart failure and myocardial infarction, pathologies often associated with low-grade inflammation. This cross-sectional study aims to investigate whether low-grade inflammation regulates SGLT2 expression and function in human vasculature, heart, and endothelial cells (ECs).
Methods and results: Human internal thoracic artery (ITA), left ventricle (LV) specimens, and cultured porcine coronary artery ECs were used. Expression of target molecules was assessed using RT-qPCR, western blot analysis, and immunofluorescence staining, and the generation of reactive oxygen species (ROS) and nitric oxide (NO) using fluorescent probes. The function of SGLT2 was investigated using empagliflozin and SGLT1 or 2 siRNA. SGLT2 mRNA and protein levels in ITA and LV specimens were correlated with the level of low-grade inflammation, markers of the angiotensin system, and EC activation. SGLT2 staining was observed in the ITA endothelium and smooth muscle, the coronary microcirculation, and cardiomyocytes. Elevated ROS formation in high SGLT2-expressing specimens was reduced by inhibition of the angiotensin system, SGLT2, and TNF-α. Exposure of ECs to IL-1ß, IL-6, and TNF-α led to an increase in SGLT1 and SGLT2 mRNA and protein expression, up-regulation of components of the angiotensin system, enhanced ROS and decreased NO formation, and activation of NF-κB. The stimulatory effect of TNF-α was prevented by N-acetylcysteine and inhibition of the angiotensin system, SGLT2 but not SGLT1, and NF-κB.
Conclusion: Low-grade inflammation is closely associated with SGLT2 expression in human vasculature and heart, and this response contributes to a feedforward mechanism with the AT1R/NADPH oxidase pathway to cause eNOS-NO/ROS imbalance.
Keywords: Cardiovascular disease; Endothelial dysfunction; Local angiotensin system; Oxidative stress; Pro-inflammatory cytokines; SGLT2.
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