Background: /Introduction: The angiotensin II (Ang II)/AT1R/NADPH oxidase-prooxidant pathway has been shown to upregulate the expression of SGLT1 and 2 and to induce premature endothelial dysfunction in coronary endothelial cells. Since all these effects are prevented by the dual SGLT1/2 inhibitor sotagliflozin (sota) and the SGLT2 inhibitor empagliflozin (empa), SGLT1 and 2 are involved in the induction of endothelial dysfunction. Purpose: The aim of the study was to evaluate the role of SGLT1 and 2 in the Ang II-induced hypertensive response leading to cardiac and vascular endothelial dysfunction. Methods: Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by plethysmography, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, fibrosis by Sirius red staining, the function of SGLT1 and 2 indirectly by the uptake of glucose-conjugated anthocyanins, and the level of oxidative stress using dihydroethidium staining. Results: The administration of Ang II to rats caused an increased systolic blood pressure from about 140 to 180 mmHg, which was not affected by empa. In the heart, the hypertensive response resulted in an increased left ventricle mass and a diastolic dysfunction as indicated by an elevated E/e' and a decreased IVRT, fibrosis and increased collagen I and ANP expression levels. In the secondary branch of the mesenteric artery, it resulted in an increased level of oxidative stress, AT1R, collagen I and of endothelial ACE, VCAM-1, MCP-1, MMP-2, MMP-9 associated with a down-regulation of eNOS. It was also associated with an increased endothelial expression level of SGLT1 in the aorta, mesenteric resistance vessel and coronary microcirculation. Moreover, an increased uptake of anthocyanins is observed in the aorta predominantly in the endothelium and this effect is markedly reduced by sota and empa. All of the above parameters were markedly reduced in the Ang II plus empa group whereas the empa treatment alone had little effect compared to the control group. Conclusion: The findings indicate that Ang II-induced hypertension promoting left ventricle cardiac dysfunction, and both macro and microvascular endothelial dysfunction are associated with an up-regulation of SGLT1 and 2 in endothelial cells. They further indicate that empa prevents the noxious impact of Ang II on the heart and vasculature despite persistent hypertension.
Cardiac diastolic dysfunction in angiotensin II treated hypertensive rats is associated with endothelial upregulation of SGLT1/2 in the macro and microcirculation: Protective effect of empagliflozin
Belcastro E;
2021-01-01
Abstract
Background: /Introduction: The angiotensin II (Ang II)/AT1R/NADPH oxidase-prooxidant pathway has been shown to upregulate the expression of SGLT1 and 2 and to induce premature endothelial dysfunction in coronary endothelial cells. Since all these effects are prevented by the dual SGLT1/2 inhibitor sotagliflozin (sota) and the SGLT2 inhibitor empagliflozin (empa), SGLT1 and 2 are involved in the induction of endothelial dysfunction. Purpose: The aim of the study was to evaluate the role of SGLT1 and 2 in the Ang II-induced hypertensive response leading to cardiac and vascular endothelial dysfunction. Methods: Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by plethysmography, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, fibrosis by Sirius red staining, the function of SGLT1 and 2 indirectly by the uptake of glucose-conjugated anthocyanins, and the level of oxidative stress using dihydroethidium staining. Results: The administration of Ang II to rats caused an increased systolic blood pressure from about 140 to 180 mmHg, which was not affected by empa. In the heart, the hypertensive response resulted in an increased left ventricle mass and a diastolic dysfunction as indicated by an elevated E/e' and a decreased IVRT, fibrosis and increased collagen I and ANP expression levels. In the secondary branch of the mesenteric artery, it resulted in an increased level of oxidative stress, AT1R, collagen I and of endothelial ACE, VCAM-1, MCP-1, MMP-2, MMP-9 associated with a down-regulation of eNOS. It was also associated with an increased endothelial expression level of SGLT1 in the aorta, mesenteric resistance vessel and coronary microcirculation. Moreover, an increased uptake of anthocyanins is observed in the aorta predominantly in the endothelium and this effect is markedly reduced by sota and empa. All of the above parameters were markedly reduced in the Ang II plus empa group whereas the empa treatment alone had little effect compared to the control group. Conclusion: The findings indicate that Ang II-induced hypertension promoting left ventricle cardiac dysfunction, and both macro and microvascular endothelial dysfunction are associated with an up-regulation of SGLT1 and 2 in endothelial cells. They further indicate that empa prevents the noxious impact of Ang II on the heart and vasculature despite persistent hypertension.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
