SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice
Rogerio?N.?Soares
;
Francisco?I.?Ramirez?Perez
;
Francisco?J.?Cabral?Amador
, et al.
Geroscience,2022,44(3):1657-1675.
DOI:
10.1007/s11357-022-00563-x
PubMed ID:
35426600
More
Abstract: Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium glucose transporter 2 (SGLT2) inhibitors is now known to decrease cardiovascular morbidity and mortality in type 2 diabetes. However, whether SGLT2 inhibition attenuates vascular aging is unknown. We first confirmed in a cohort of adult subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether SGLT2 inhibition with empagliflozin (Empa) ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. Specifically, we assessed mesenteric artery endothelial function and stiffness (via flow-mediated dilation and pressure myography mechanical responses, respectively) and aortic stiffness (in vivo via pulse wave velocity and ex vivo via atomic force microscopy) in Empa-treated (14 mg/kg/day for 6 weeks) and control 80-week-old C57BL/6 J male mice. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Additionally, Empa-treated mice had greater vascular endothelial nitric oxide synthase activation, lower phosphorylated cofilin, and filamentous actin content, with downregulation of pathways involved in production of reactive oxygen species. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of CVD in older individuals.
Keywords:
SGLT2 ;
Arterial stifness ;
Aging ;
Endothelial function ;
Oxidative stress
Purchased from AmBeed:
864070-44-0
Empagliflozin Relaxes Resistance Mesenteric Arteries by Stimulating Multiple Smooth Muscle Cell Voltage-Gated K+ (KV) Channels
Hasan, Ahasanul
;
Hasan, Raquibul
;
Int. J. Mol. Sci.,2021,22(19):10842.
DOI:
10.3390/ijms221910842
PubMed ID:
34639181
More
Abstract: The antidiabetic drug empagliflozin is reported to produce a range of cardiovascular effects, including a reduction in systemic blood pressure. However, whether empagliflozin directly modulates the contractility of resistance-size mesenteric arteries remains unclear. Here, we sought to investigate if empagliflozin could relax resistance-size rat mesenteric arteries and the associated underlying mol. mechanisms. We found that acute empagliflozin application produces a concentration-dependent vasodilation in myogenic, depolarized and phenylephrine (PE)-preconstricted mesenteric arteries. Selective inhibition of smooth muscle cell voltage-gated K+ channels KV1.5 and KV7 abolished empagliflozin-induced vasodilation. In contrast, pharmacol. inhibition of large-conductance Ca2+-activated K+ (BKCa) channels and ATP-sensitive (KATP) channels did not abolish vasodilation. Inhibition of the vasodilatory signaling axis involving endothelial nitric oxide (NO), smooth muscle cell soluble guanylyl cyclase (sGC) and protein kinase G (PKG) did not abolish empagliflozin-evoked vasodilation. Inhibition of the endothelium-derived vasodilatory mol. prostacyclin (PGI2) had no effect on the vasodilation. Consistently, empagliflozin-evoked vasodilation remained unaltered by endothelium denudation. Overall, our data suggest that empagliflozin stimulates smooth muscle cell KV channels KV1.5 and KV7, resulting in vasodilation in resistance-size mesenteric arteries. This study demonstrates for the first time a novel mechanism whereby empagliflozin regulates arterial contractility, resulting in vasodilation. Due to known antihypertensive properties, treatment with empagliflozin may complement conventional antihypertensive therapy.
Keywords:
empagliflozin ;
mesenteric arteries ;
smooth muscle cell ;
vasodilation ;
voltage-gated K+ channels
Purchased from AmBeed:
864070-44-0
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Empagliflozin improves post-infarction cardiac remodeling through GTP enzyme cyclohydrolase 1 and irrespective of diabetes status
Asensio Lopez, Maria del Carmen
;
Lax, Antonio
;
Hernandez Vicente, Alvaro
, et al.
SCI REP-UK,2020,10(1):13553.
DOI:
10.1038/s41598-020-70454-8
PubMed ID:
32782412
More
Abstract: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown to prevent heart failure progression, although the mechanisms remain poorly understood. Here we evaluated the effect of empagliflozin (EMPA, SGLT2i) in cardiac remodeling after myocardial infarction, the interplay with diabetes status and the role of cardiac GTP enzyme cyclohydrolase 1 (cGCH1). A rat model of diabetes (50 mg/kg streptozotocin, i.p.) was subjected to myocardial infarction and left ventricular systolic dysfunction, by ligation of the left anterior descending coronary artery. EMPA therapy significantly improved cardiac remodeling parameters and ameliorated processes of fibrosis and hypertrophy, in both non-diabetic and diabetic rats. This cardioprotective effect related with a significant increase in myocardial expression levels of cGCH1, which led to activation of nNOS and eNOS, and inhibition of iNOS, and subsequently resulted in increasing of NO levels and decreasing O2.- and nitrotyrosine levels. These effects were replicated in a cardiomyocyte biomech. stretching diabetic model, where silencing cGCH1 blocked the preventive effect of EMPA. The beneficial effects were observed irresp. of diabetes status, although the magnitude was greater in presence of diabetes. Empagliflozin improves myocardial remodeling after myocardial infarction through overexpression of cGCH1, and irresp. of diabetes status.
Purchased from AmBeed:
864070-44-0
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