Angiotensin II-induced upregulation of SGLT1 and 2 contributes to human microparticle‐stimulated endothelial senescence and dysfunction: protective effect of gliflozins

Abstract

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular risk in type 2 diabetes patients independently of glycemic control. Although angiotensin II (Ang II) and blood-derived microparticles are major mediators of cardiovascular disease, their impact on SGLT1 and 2 expression and function in endothelial cells (ECs) and isolated arteries remains unclear. Methods ECs were isolated from porcine coronary arteries, and arterial segments from rats. The protein expression level was assessed by Western blot analysis and immunofluorescence staining, mRNA levels by RT-PCR, oxidative stress using dihydroethidium, nitric oxide using DAF-FM diacetate, senescence by senescence-associated beta-galactosidase activity, and platelet aggregation by aggregometer. Microparticles were collected from blood of patients with coronary artery disease (CAD-MPs). Results Ang II up-regulated SGLT1 and 2 protein levels in ECs, and caused a sustained extracellular glucose- and Na+-dependent pro-oxidant response that was inhibited by the NADPH oxidase inhibitor VAS-2780, the AT1R antagonist losartan, sotagliflozin (Sota, SGLT1 and SGLT2 inhibitor), and empagliflozin (Empa, SGLT2 inhibitor). Ang II increased senescence-associated beta-galactosidase activity and markers, VCAM-1, MCP-1, tissue factor, ACE, and AT1R, and down-regulated eNOS and NO formation, which were inhibited by Sota and Empa. Increased SGLT1 and SGLT2 protein levels were observed in the rat aortic arch, and Ang II- and eNOS inhibitor-treated thoracic aorta segments, and were associated with enhanced levels of oxidative stress and prevented by VAS-2780, losartan, Sota and Empa. CAD-MPs promoted increased levels of SGLT1, SGLT2 and VCAM-1, and decreased eNOS and NO formation in ECs, which were inhibited by VAS-2780, losartan, Sota and Empa. Conclusions Ang II up-regulates SGLT1 and 2 protein expression in ECs and arterial segments to promote sustained oxidative stress, senescence and dysfunction. Such a sequence contributes to CAD-MPs-induced endothelial dysfunction. Since AT1R/NADPH oxidase/SGLT1 and 2 pathways promote endothelial dysfunction, inhibition of SGLT1 and/or 2 appears as an attractive strategy to enhance the protective endothelial function.

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

“…Individuals carrying loss-of-function mutations in the SGLT1 gene are estimated to have a lower risk of developing heart failure, driven by mitigation of postprandial hyperglycemic episodes ( Seidelmann et al, 2018 ). In endothelial cells, angiotensin II upregulates SGLT1 expression to promote sustained oxidative stress, and inhibition of SGLT1 appears to be an attractive strategy to enhance protective endothelial function ( Park et al, 2021 ). Apart from cardiomyocytes and endothelial cells in the heart, we first identified that SGLT1 was expressed in human CFs ( Meng et al, 2018 ), and in the present study, the significant finding was that an increase in SGLT1 expression in rat hearts triggered the development of cardiac fibrosis through activation of CFs by upregulating the p38 MAPK and ERK1/2 signaling pathways.…”

Circulating extracellular vesicles during pregnancy in women with type 1 diabetes: a secondary analysis of the CONCEPTT trial

“…Previous studies have shown that EVs induce endothelial inflammation, haemostasis, angiogenesis, and endothelial dysfunction [ 35 ]. Thus, in addition to serving as biomarkers of vascular injury they may actually induce vascular dysfunction through direct actions on endothelial cells leading to increased oxidative stress, inflammation, and impaired endothelium-dependent vasorelaxation [ 24 , 36 – 40 ]. We and others have previously shown that endothelial EVs exert greater deleterious effects on the endothelium when formed under hyperglycaemic conditions [ 24 , 41 ].…”

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

“…A recent study by Park et al extended these findings, observing that AngII was a potent inducer of SGLT1 and SGLT2 in ECs isolated from porcine coronary arteries, independently of hyperglycemia, and that these receptors had a key role to promote ultimately pro-oxidant response and endothelial deleterious effects. Interestingly, both sotagliflozin and empagliflozin prevented these effects [115].…”