Vascular Dysfunction in Diabetes Mellitus

Gutterman, David D.; Durand, Matthew J.

doi:10.1161/circresaha.114.303203

Cited by 6 publications

(6 citation statements)

References 30 publications

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“…9) in cerebral arteries isolated from normal control rats. Our results are in agreement with previous report that hyperglycemia impaired BK Ca β1-subunit, which led to the diabetic vascular dysfunction (Dong et al 2008, Gutterman & Durand 2014, Nystoriak et al 2014, Yi et al 2014.…”

Section: Figuresupporting

confidence: 94%

“…It has been demonstrated that hyperglycemia directly impaired vasodilation by impairing BK Ca channel in smooth muscle, and then led to the hypertension in diabetes (Tousoulis et al 2013, Fernández-Velasco et al 2014, Gutterman & Durand 2014. BK Ca channel is an important protective mechanism to regulate the dynamic equilibrium between vascular constriction and relaxation (Lazuko et al 2014).…”

Section: Hyperglycemia Hypertension and Impaired Bk Ca Channel In DImentioning

confidence: 99%

“…BK Ca channel is an important protective mechanism to regulate the dynamic equilibrium between vascular constriction and relaxation (Lazuko et al 2014). Activation of BK Ca channel induces K + efflux and promotes VSMC relaxation by limiting Ca 2+ influx (Gutterman & Durand 2014, Nystoriak et al 2014, Yi et al 2014. Vascular BK Ca channel is composed of pore-forming α-subunit and accessory β1-subunit.…”

Section: Hyperglycemia Hypertension and Impaired Bk Ca Channel In DImentioning

confidence: 99%

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Berberine reduced blood pressure and improved vasodilation in diabetic rats

Liang

Zhang

et al. 2017

Journal of Molecular Endocrinology

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Hyperglycemia and hypertension are considered to be the two leading risk factors for vascular disease in diabetic patients. However, few pharmacologic agents could provide a combinational therapy for controlling hyperglycemia and hypertension at the same time in diabetes. The objectives of this study are to investigate whether berberine treatment could directly reduce blood pressure and identify the molecular mechanism underlying the vascular protection of berberine in diabetic rats. Berberine was intragastrically administered with different dosages of 50, 100 and 200 mg/kg/day to diabetic rats for 8 weeks since the injection of streptozotocin. The endothelium-dependent/-independent relaxation in middle cerebral arteries was investigated. The activity of large-conductance Ca-activated K channel (BK) was investigated by recording whole-cell currents, analyzing single-channel activities and assessing the expressions of α- and β1-subunit at protein or mRNA levels. Results of the study suggest that chronic administration of 100 mg/kg/day berberine not only lowered blood glucose but also reduced blood pressure and improved vasodilation in diabetic rats. Furthermore, berberine markedly increased the function and expression of BK β1-subunit in cerebral vascular smooth muscle cells (VSMCs) isolated from diabetic rats or when exposed to hyperglycemia condition. The present study provided initial evidences that berberine reduced blood pressure and improved vasodilation in diabetic rats by activation of BK channel in VSMCs, which suggested that berberine might provide a combinational therapy for controlling hyperglycemia and blood pressure in diabetes. Furthermore, our work indicated that activation of BK channel might be the underlying mechanism responsible for the vascular protection of berberine in diabetes.

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Section: Figuresupporting

confidence: 94%

Section: Hyperglycemia Hypertension and Impaired Bk Ca Channel In DImentioning

confidence: 99%

Section: Hyperglycemia Hypertension and Impaired Bk Ca Channel In DImentioning

confidence: 99%

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Berberine reduced blood pressure and improved vasodilation in diabetic rats

Liang

Zhang

et al. 2017

Journal of Molecular Endocrinology

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“…It is well established that impaired vascular BK channel function is a common feature in both type 1 and type 2 diabetes, which are associated with decreased BK-β1 expression in diabetic vessels. 1,8 We found that Sorbs2 protein expression was reduced by 60% in the coronary arteries of db/db diabetic mice (Figure 8A), concomitant with a significant reduction in the cytosolic and surface expression of BK-α by 76.0% and 84.6%, respectively, as well as the cytosolic and surface expression of BK-β1 by 57.3% and 42.4%, respectively (Figure 8B). BK channel current density in freshly isolated coronary SMCs and BK channel-mediated vasodilation in coronary arteries were diminished in db/db diabetic mice, compared with those of Lean control mice (Figure 8C and 8D).…”

Section: Downregulation Of Sorbs2 Expression In the Arteries Of Diabe...mentioning

confidence: 93%

“…7 We have reported that BK-β1 expression is downregulated in diabetic vessels, contributing to vascular dysfunction in both type 1 and type 2 diabetes. 1,8 Moreover, the Nrf2 (nuclear factor erythroid-2-related factor 2) signaling, which regulates the Kcnma1 transcription, is significantly downregulated, leading to vascular BK channel dysregulation in diabetes. 9,10 However, the mechanisms that underlie vascular BK channel pathophysiology in diabetes remain largely unknown.…”

mentioning

confidence: 99%

Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes

Sun,

Lee,

2024

Circulation Research

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Background: Vascular BK channel, composed of the large conductance Ca 2+ -activated K + channel αsubunit and the large conductance Ca 2+ -activated K + channel β1 subunits, is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbin homology and Sorbs2 (SH3 [Src homology 3] domain-containing protein 2) are ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown. Methods: The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis. Results: Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and the Kcnma1 (encoding the large conductance Ca 2+ -activated K + channel αsubunit) mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with the large conductance Ca 2+ -activated K + channel αsubunit, while both the SH3 and Sorbin homology domains of Sorbs2 interact with the large conductance Ca 2+ -activated K + channel β1 subunit. Deletion of the SH3 or Sorbin homology domains abolishes the Sorbs2 effect on the large conductance Ca 2+ -activated K + channel αsubunit/the large conductance Ca 2+ -activated K + channel β1 subunit current density. Additionally, Sorbs2 is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of Sorbs2 and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that Sorbs2 knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca 2+ -sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice. Conclusions: Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.

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Salidroside improved cerebrovascular vasodilation in streptozotocin-induced diabetic rats through restoring the function of BKCa channel in smooth muscle cells

Wang

Zhang

et al. 2017

Cell Tissue Res

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Vessel disease is a kind of severe complication in diabetic patients. However, few pharmacologic agents can directly recover diabetic vascular function. Salidroside (SAL), a major ingredient from Rhodiola rosea, has been found to have an obvious hypoglycemic effect and a beneficial protection on vascular function in diabetes. However, whether SAL is a suitable treatment for diabetes has not so far been evaluated and the underlying mechanisms remain unknown. The present work aims to (1) investigate the potential effects of SAL on cerebrovascular relaxation in streptozotocin-induced diabetic rats or when exposed to acute hyperglycemia condition and (2) examine whether function of the BK channel is involved in SAL treatment for diabetic vascular relaxation. Our results indicate that chronic administration of 100 mg/kg/day SAL not only improves cerebrovascular relaxation but also increases BK β1-subunit expressions at both protein and mRNA levels and enhances BK whole-cell and single-channel activities in cerebral VSMCs of diabetic rats. Correspondingly, acute application of 100 μM SAL induces cerebrovascular relaxation by activation of the BK channel. Furthermore, SAL activated the BK channel mainly through acting on the β1-subunit in HEK293 cells transfected with hSloα+β1 constructs. We concluded that SAL improved vasodilation in diabetic rats through restoring the function of the BK-β1 subunit in cerebrovascular smooth muscle cells, which may be the underlying mechanism responsible for the vascular protection of SAL in diabetes.

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Vascular Dysfunction in Diabetes Mellitus

Cited by 6 publications

References 30 publications

Berberine reduced blood pressure and improved vasodilation in diabetic rats

Berberine reduced blood pressure and improved vasodilation in diabetic rats

Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes

Salidroside improved cerebrovascular vasodilation in streptozotocin-induced diabetic rats through restoring the function of BKCa channel in smooth muscle cells

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