Angiotensin II‐induced redox‐sensitive SGLT1 and 2 expression promotes high glucose‐induced endothelial cell senescence

Abstract

High glucose (HG)‐induced endothelial senescence and dysfunction contribute to the increased cardiovascular risk in diabetes. Empagliflozin, a selective sodium glucose co‐transporter2 (SGLT2) inhibitor, reduced the risk of cardiovascular mortality in type 2 diabetic patients but the protective mechanism remains unclear. This study examines the role of SGLT2 in HG‐induced endothelial senescence and dysfunction. Porcine coronary artery cultured endothelial cells (ECs) or segments were exposed to HG (25 mmol/L) before determination of senescence‐associated beta‐galactosidase activity, protein level by Western blot and immunofluorescence staining, mRNA by RT‐PCR, nitric oxide (NO) by electron paramagnetic resonance, oxidative stress using dihydroethidium and glucose uptake using 2‐NBD‐glucose. HG increased ECs senescence markers and oxidative stress, down‐regulated eNOS expression and NO formation, and induced the expression of VCAM‐1, tissue factor, and the local angiotensin system, all these effects were prevented by empagliflozin. Empagliflozin and LX‐4211 (dual SGLT1/2 inhibitor) reduced glucose uptake stimulated by HG and H2O2 in ECs. HG increased SGLT1 and 2 protein levels in cultured ECs and native endothelium. Inhibition of the angiotensin system prevented HG‐induced ECs senescence and SGLT1 and 2 expression. Thus, HG‐induced ECs ageing is driven by the local angiotensin system via the redox‐sensitive up‐regulation of SGLT1 and 2, and, in turn, enhanced glucotoxicity.

Empagliflozin improved systolic blood pressure, endothelial dysfunction and heart remodeling in the metabolic syndrome ZSF1 rat

“…The present findings indicate that the empagliflozin treatment was able to normalize the expression level of senescence markers, eNOS, tissue factor, VCAM-1 and SGLT1 and 2 in the inner aortic arch curvature to levels similar to those in the outer aortic arch curvature, which is protected by the exposure to high levels of shear stress. Thus, these observations suggest that empagliflozin might possibly contribute to protect arterial sites of atherogenesis by blunting the SGLT2-mediated pro-senescent and pro-atherothrombotic responses [30]. The fact that no such differences in the expression level of pro-atherothrombotic markers are observed in the inner and outer curvature of the obese ZSF1 rat suggests that the responsiveness of the arterial wall to local blood flow behavior appears to be altered possibly due to the chronic exposure of metabolic stress.…”

“…Several potential mechanism, besides glycemic control, have been suggested such as the involvement of visceral adiposity, body weight, hyperinsulinemia, blood pressure, arterial stiffness, lipid profile, and albuminuria [34]. In addition, SGLT1 and 2 expression has been observed in cultured and native ECs under pathological conditions such as hyperglycemic state and oxidative stress, promoting endothelial senescence and dysfunction subsequent to excessive glucose entry [30]. Since all of these effects were inhibited by empagliflozin, SGLT2 inhibitors may possibly also contribute to protect the cardiovascular system by targeting the pivotal endothelial function [30].…”

“…In addition, SGLT1 and 2 expression has been observed in cultured and native ECs under pathological conditions such as hyperglycemic state and oxidative stress, promoting endothelial senescence and dysfunction subsequent to excessive glucose entry [30]. Since all of these effects were inhibited by empagliflozin, SGLT2 inhibitors may possibly also contribute to protect the cardiovascular system by targeting the pivotal endothelial function [30]. Therefore, the present study has evaluated the impact of empagliflozin on the cardiovascular system in an experimental model of metabolic syndrome with HFpEF, the ZSF1 rat, which combines several major cardiovascular risk factors including obesity, hypertension, diabetes and dyslipidemia [35][36][37].…”

“…Finally, empagliflozin ameliorated kidney injury in T2D female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness [29]. In addition, a redox-sensitive up-regulation of SGLT1 and 2 has been observed in coronary artery ECs in response to high glucose and H 2 O 2 leading to enhanced glucose uptake and induction of atherothrombotic responses [30]. Altogether, these findings support the concept that gliflozins protect the cardiovascular system, besides the improvement of the glycemic control, possibly also by targeting the cardiovascular and, in particular, the pivotal protective endothelial function.…”

Accelerated Kidney Aging in Diabetes Mellitus

“…This result indicates that SGLT2 inhibitors might be the new hope of the patients with DN after the use of renin-angiotensin system blockers over the past 18 years. The underlying mechanism may be related to its antisenescence of renal cells resulting from the fact that SGLT2 increased the expression of senescent markers in proximal tubules [76] and endothelial cells [192] in DM, indicating that SGLT2 inhibitors might retard renal accelerated aging in DM to preserve kidney function. Other antidiabetic agents reported to protect against accelerated aging are dipeptidyl peptidase 4 (DPP4) inhibition and GLP-1 receptor agonists, which act on the modulation of incretin that protect against age-related diseases including DN [193].…”