scholarly journals AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Paz Prada ◽  
Arsalan U. Syed ◽  
Gopireddy R. Reddy ◽  
Miguel Martín-Aragón Baudel ◽  
Víctor A. Flores-Tamez ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Vascular Complications ◽  
Channel Activity ◽  
Camp Synthesis ◽  
Anchoring Protein ◽  
Extracellular Glucose ◽  
Elevated Glucose ◽  
Underlying Mechanisms ◽  
Purinergic Modulation ◽  
Human And Mouse

Abstract The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia.

Mechanisms underlying heart failure in type 2 diabetes mellitus

2019 ◽  
pp. 37-39
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Experimental Studies ◽  
Vascular Complications ◽  
Molecular Alterations ◽  
Increased Risk ◽  
Cardioprotective Effects ◽  
Underlying Mechanisms ◽  
Cardio Vascular

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

Abstract P204: Epithelial Sodium Channel Stimulation by Glucose

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Parijat S Joy ◽  
Peter M. Snyder
Keyword(s):  
Diabetes Mellitus ◽  
Cell Surface ◽  
Collecting Duct ◽  
Short Circuit ◽  
Primary Cultures ◽  
Endocytic Pathway ◽  
Sodium Absorption ◽  
Dependent Manner ◽  
Elevated Glucose ◽  
Underlying Mechanisms

There is a link between diabetes mellitus and hypertension, but the underlying mechanisms are poorly understood. The epithelial Na + channel ENaC plays an important role in blood pressure control; ENaC mutations cause Liddle’s syndrome, an inherited form of hypertension. Previous work suggests that ENaC abundance is increased in diabetes mellitus, but the underlying mechanisms are unclear. Here we tested the effect of glucose on ENaC regulation. In Ussing chamber experiments using mouse kidney collecting duct cells (mCCD) and primary cultures of human lung epithelia, elevated glucose increased ENaC-mediated short-circuit current by 2-3 times in a dose-dependent manner from 100mg/dl to 400mg/dl of glucose. This was caused by an increase in ENaC abundance at the cell surface. We hypothesized that hyperglycemia might enhance ENaC cell surface abundance by altering activity of Nedd4-2, an E3 ubiquitin-protein ligase that binds to PY motifs within ENaC. Consistent with this hypothesis, we found that mutation of the PY motifs abolished ENaC stimulation by elevated glucose. Moreover, using a biotinylation assay, we found that elevated glucose (300 mg/dl) slowed ENaC endocytosis and reduced its degradation in the endocytic pathway. These changes in trafficking are explained by our finding that glucose reduced ENaC binding to Nedd4-2, and hence, reduced ENaC ubiquitination. O-GlcNAcylation plays a role in insulin signaling and glucose toxicity due to increased O-GlcNAcylation of target proteins. To test a role for O-GlcNAcylation in ENaC stimulation by glucose, we used 6-Diazo-5-oxo-l-norleucine (DON) to inhibit O-GlcNAcylation. DON abolished ENaC stimulation by elevated glucose. Using anti-O-GlcNAc antibody, we found that Nedd4-2 is a substrate for O-GlcNAcylation, and this modification was increased by elevated glucose. DON also reversed the reduction in binding of Nedd4-2 to ENaC at high glucose levels. Together, our data suggest a model in which hyperglycemia stimulates ENaC through O-GlcNAcylation of Nedd4-2, increasing ENaC abundance at cell surface thus increasing epithelial sodium absorption.

scholarly journals Vascular-dependent effects of elevated glucose on postganglionic sympathetic neurons

2011 ◽  
Vol 300 (4) ◽  
pp. H1386-H1392 ◽  
Author(s):  
Deborah H. Damon
Keyword(s):  
Vascular Function ◽  
Sympathetic Neurons ◽  
Vascular Complications ◽  
Sympathetic Nerves ◽  
T Test ◽  
Neuronal Cultures ◽  
Elevated Glucose ◽  
Low Glucose

Perivascular sympathetic nerves are important determinants of vascular function that are likely to contribute to vascular complications associated with hyperglycemia and diabetes. The present study tested the hypothesis that glucose modulates perivascular sympathetic nerves by studying the effects of 7 days of hyperglycemia on norepinephrine (NE) synthesis [tyrosine hydroxylase (TH)], release, and uptake. Direct and vascular-dependent effects were studied in vitro in neuronal and neurovascular cultures. Effects were also studied in vivo in rats made hyperglycemic (blood glucose >296 mg/dl) with streptozotocin (50 mg/kg). In neuronal cultures, TH and NE uptake measured in neurons grown in high glucose (HG; 25 mM) were less than that in neurons grown in low glucose (LG; 5 mM) ( P < 0.05; n = 4 and 6, respectively). In neurovascular cultures, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release from neurovascular cultures grown in HG (1.8 ± 0.2%; n = 5) was greater than that from cultures grown in LG (0.37 ± 0.28%; n = 5; P < 0.05; unpaired t-test). In vivo, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release in hyperglycemic animals (9.4 + 1.1%; n = 6) was greater than that in control animals (5.39 + 1.1%; n = 6; P < 0.05; unpaired t-test). These data identify a novel vascular-dependent effect of elevated glucose on postganglionic sympathetic neurons that is likely to affect the function of perivascular sympathetic nerves and thereby affect vascular function.

scholarly journals Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release

2019 ◽  
Vol 151 (9) ◽  
Author(s):  
Geoffrey Denwood ◽  
Andrei Tarasov ◽  
Albert Salehi ◽  
Elisa Vergari ◽  
Reshma Ramracheya ◽  
...  
Keyword(s):  
Electrical Activity ◽  
Secretory Vesicles ◽  
Glucose Levels ◽  
Somatostatin Secretion ◽  
Elevated Glucose ◽  
Mouse Islets ◽  
Underlying Mechanisms ◽  
Fold Stimulation ◽  
Cyclase Activator ◽  
Stimulation Of

Somatostatin secretion from pancreatic islet δ-cells is stimulated by elevated glucose levels, but the underlying mechanisms have only partially been elucidated. Here we show that glucose-induced somatostatin secretion (GISS) involves both membrane potential-dependent and -independent pathways. Although glucose-induced electrical activity triggers somatostatin release, the sugar also stimulates GISS via a cAMP-dependent stimulation of CICR and exocytosis of somatostatin. The latter effect is more quantitatively important and in mouse islets depolarized by 70 mM extracellular K+, increasing glucose from 1 mM to 20 mM produced an ∼3.5-fold stimulation of somatostatin secretion, an effect that was mimicked by the application of the adenylyl cyclase activator forskolin. Inhibiting cAMP-dependent pathways with PKI or ESI-05, which inhibit PKA and exchange protein directly activated by cAMP 2 (Epac2), respectively, reduced glucose/forskolin-induced somatostatin secretion. Ryanodine produced a similar effect that was not additive to that of the PKA or Epac2 inhibitors. Intracellular application of cAMP produced a concentration-dependent stimulation of somatostatin exocytosis and elevation of cytoplasmic Ca2+ ([Ca2+]i). Both effects were inhibited by ESI-05 and thapsigargin (an inhibitor of SERCA). By contrast, inhibition of PKA suppressed δ-cell exocytosis without affecting [Ca2+]i. Simultaneous recordings of electrical activity and [Ca2+]i in δ-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+]i spikes did not correlate with δ-cell electrical activity but instead reflected Ca2+ release from the ER. These spontaneous [Ca2+]i spikes are resistant to PKI but sensitive to ESI-05 or thapsigargin. We propose that cAMP links an increase in plasma glucose to stimulation of somatostatin secretion by promoting CICR, thus evoking exocytosis of somatostatin-containing secretory vesicles in the δ-cell.

Endothelin-mediated in vivo pressor responses following TRPV1 activation

2011 ◽  
Vol 301 (3) ◽  
pp. H1135-H1142 ◽  
Author(s):  
Vahagn A. Ohanyan ◽  
Giacinta Guarini ◽  
Charles K. Thodeti ◽  
Phani K. Talasila ◽  
Priya Raman ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Receptor Potential ◽  
Immunoblot Analysis ◽  
Trpv1 Channels ◽  
Transient Receptor

Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1(−/−)], db/ db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the α-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 μg/kg) dose dependently increased MAP in control mice (5.7 ± 1.6, 11.7 ± 2.1, 25.4 ± 3.4, and 51.6 ± 3.9%), which was attenuated in db/db mice (3.4 ± 2.1, 3.9 ± 2.1, 7.0 ± 3.3, and 17.9 ± 6.2%). TRPV1(−/−) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ETA /ETB). Inhibition of ETA receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ETA and ETB receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ETA receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.

scholarly journals Hypertension Secondary to PHPT: Cause or Coincidence?

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Helmut Schiffl ◽  
Susanne M. Lang
Keyword(s):  
Cardiovascular Reactivity ◽  
Vascular Reactivity ◽  
Cytosolic Calcium ◽  
Free Calcium ◽  
Normal Blood Pressure ◽  
Cytosolic Free Calcium ◽  
Hypertensive Patients ◽  
Before And After ◽  
Underlying Mechanisms ◽  
Normal Controls

Primary hyperparathyroidism (PHPT) may be associated with arterial hypertension. The underlying mechanisms are not fully understood and reversibility by parathyroid surgery is controversial. This study aimed to characterize pressor hormones, vascular reactivity to norepinephrine, and cytosolic-free calcium in platelets in 15 hypertensive patients with hypercalcaemic PHPT before and after successful parathyroidectomy and to compare them with 5 pre-hypertensive patients with normocalcaemic PHPT, 8 normotensive patients with hypercalcaemic PHPT and 15 normal controls. Hypertensive patients with hypercalcaemic PHPT had slightly higher levels of pressor hormones (), enhanced cardiovascular reactivity to norepinephrine () and increased cytosolic calcium in platelets () than controls. Pre-hypertensive patients with normocalcaemic PHPT had intermediate values of increased cardiovascular reactivity and cytosolic calcium. Normotensive patients with hypercalcaemic PHPT and normotensive controls had comparable pressor hormone concentrations and intracellular calcium levels. Successful parathyroidectomy was associated with normal blood pressure values and normalisation of pressor hormone concentrations, cardiovascular pressor reactivity and cytosolic free calcium. Our results suggest that parathyroid hypertension is mediated/maintained, at least in part, by functional alterations of vascular smooth muscle cells and can be cured by parathyroidectomy in those patients who do not have primary hypertension.

LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

Omega-3E treatment regulates matrix metalloproteinases and prevents vascular reactivity alterations in diabetic rat aortaThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

2009 ◽  
Vol 87 (12) ◽  
pp. 1063-1073 ◽  
Author(s):  
Esma N. Zeydanli ◽  
Belma Turan
Keyword(s):  
Matrix Metalloproteinases ◽  
Vascular Reactivity ◽  
Vascular System ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Close Correlation ◽  
Tissue Level ◽  
Rat Aorta ◽  
Diabetic Rat ◽  
Cardiovascular Research

It is known that increased generation of oxidants and (or) reduced endogenous antioxidant defense mechanisms are associated with the etiology of diabetic vascular complications. Although a close correlation exists between increased oxidative stress and the activation of matrix metalloproteinases (MMPs), little is known about the effect of hyperglycemia on the regulation and contribution of MMPs in the vascular system. Therefore, we aimed to examine whether omega-3E (50 mg/kg per day for 4 weeks), a long-chain (n-3) polyunsaturated fatty acid enriched with vitamin E, has a beneficial effect on vascular dysfunction via affecting MMPs in streptozotocin-diabetic rat aorta. Omega-3E treatment improved the diabetes-induced impairment of phenylephrine-induced contraction and isoproterenol-induced relaxation responses of aorta. It also exhibited marked protection against diabetes-induced degenerative changes in smooth muscle cell morphology. Biochemical data showed that this treatment significantly prevented important changes, such as inhibition of MMP-2 and MMP-9 activity, loss of tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) protein, increase in tissue levels of thiol oxidation, endothelin-1, protein kinase C (PKC), and cAMP production, and decrease in tissue level of nitrite. These results indicated that omega-3E significantly improved impaired vascular responses and regulated the activity of MMPs via preventing oxidative injury. Overall, the data suggest that omega-3E ameliorates or prevents vascular reactivity alterations in diabetes. Such an observation provides preliminary evidence for omega-3E’s potential as a therapeutic agent for the prevention of vascular disorders in diabetes.

Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome

2010 ◽  
Vol 299 (6) ◽  
pp. E947-E952 ◽  
Author(s):  
Francesca Schinzari ◽  
Manfredi Tesauro ◽  
Valentina Rovella ◽  
Angelica Galli ◽  
Nadia Mores ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Vitamin C ◽  
Vascular Reactivity ◽  
Vascular Complications ◽  
Glucose Disposal ◽  
Vascular Abnormalities ◽  
Insulin Resistant ◽  
The Metabolic Syndrome ◽  
Before And After

Defective insulin-dependent vasodilation might contribute importantly to metabolic and vascular abnormalities of the metabolic syndrome (MetS). However, despite extensive investigation, the precise mechanisms involved in insulin's vasoactive effects have not been fully elucidated. Therefore, this study sought to better characterize insulin's physiological actions on vascular reactivity and their potential derangement in the MetS. Forearm blood flow responses to graded doses of acetylcholine, sodium nitroprusside, and verapamil were assessed by strain-gauge plethysmography in patients with obesity-related MetS ( n = 20) and in matched controls ( n = 18) before and after intra-arterial infusion of insulin (0.2 mU·kg−1·min−1). Possible involvement of increased oxidative stress in the impaired insulin-stimulated vasodilator responsiveness of patients with MetS ( n = 12) was also investigated using vitamin C (25 mg/min). In control subjects, significant potentiation of the vasodilator responses to acetylcholine, nitroprusside, and verapamil was observed after insulin infusion (all P < 0.05). However, no significant change in vasodilator reactivity to either of these drugs was observed following hyperinsulinemia in patients with MetS (all P > 0.05). Interestingly, administration of vitamin C to patients with MetS during hyperinsulinemia significantly enhanced the vasodilator responsiveness to acetylcholine, nitroprusside, and verapamil (all P < 0.05 vs. hyperinsulinemia alone). In conclusion, insulin exerts a generalized facilitatory action on vasodilator reactivity, and this effect is impaired in patients with MetS likely because of increased oxidative stress. Given the importance of vasodilator reactivity in affecting glucose disposal and vascular homeostasis, this defect may then contribute to the development of metabolic and vascular complications in insulin-resistant states.

Increased Na+ intake during gestation in rats is associated with enhanced vascular reactivity and alterations of K+ and Ca2+ function

2004 ◽  
Vol 287 (4) ◽  
pp. H1848-H1856 ◽  
Author(s):  
Karine Auger ◽  
Annie Beauséjour ◽  
Michèle Brochu ◽  
Jean St-Louis
Keyword(s):  
Vascular Reactivity ◽  
Channel Blocker ◽  
Gestational Hypertension ◽  
Sodium Intake ◽  
Physiological Changes ◽  
Channel Activity ◽  
Pregnant Rats ◽  
Regular Diet ◽  
Channel Activator ◽  
Sodium Supplementation

Gestation is associated with decreased blood pressure and resistance to the effects of vasoconstrictor agents. A recent study showed that pregnant rats, on increased sodium intake, present physiological changes that resemble those observed in preeclampsia. We investigated the effects of sodium supplementation on reactivity and on potassium and Ca2+ channel activity in blood vessels during gestation. Sodium supplements, 0.9% or 1.8% NaCl as drinking water, were given to nonpregnant and pregnant rats for 7 days (last week of gestation). Reactivity to phenylephrine (PE), KCl, arginine vasopressin (AVP), and tetraethylammonium (TEA) was measured in aortic rings under modulation of potassium and calcium channels. TEA, a nonselective K+ channel inhibitor, induced concentration-dependent responses in aortic rings from nonpregnant but not in those from pregnant rats. The response to TEA was restored in rings from pregnant rats after preincubation with 10 mmol/l KCl. Sodium supplementation did not affect the response to TEA in the aortas of pregnant animals. After sodium supplementation, maximum responses to PE and AVP were decreased and increased in aortic rings from nonpregnant and pregnant rats, respectively. Cromakalim (an ATP-sensitive K+ channel activator)-induced inhibition of the responses to the three vasoconstrictors was more striking in aorta from nonpregnant than pregnant rats on regular diet, whereas it produced similar inhibition in tissues from both groups of animals on 0.9% and 1.8% NaCl. NS-1619 (a Ca2+-sensitive K+ activator) elicited heightened effects in the aortas of pregnant animals receiving 0.9% NaCl supplementation. Nifedipine (a Ca2+ channel blocker) caused greater inhibition of the contractile responses in tissues from nonpregnant rats on regular diet, and its action was increased in pregnant rats on sodium-supplemented diets. These data demonstrate that augmented sodium intake during gestation in the rat is linked with the reversal of gestational-associated resistance to vasopressors and indicate that this is an experimental model showing some features of gestational hypertension.

Sign in / Sign up

Export Citation Format

Share Document