Biphasic increase of gap junction coupling induced by dipyridamole in the rat aortic A-10 vascular smooth muscle cell line

Begandt, Daniela; Bader, Almke; Dreyer, Lutz; Eisert, Natalie; Reeck, Thilo; Ngezahayo, Anaclet

doi:10.1007/s12079-013-0196-4

Cited by 9 publications

(6 citation statements)

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“…) and smooth muscle cells (Begandt et al . ), the mechanisms of cAMP regulation of Cx36 coupling in β‐cells has not been directly studied. Changes in Cx36 turnover may reflect a number of regulatory mechanisms, including Cx36 gene expression, Cx36 trafficking to the membrane, recruitment and assembly of Cx36 into gap junction plaques, and endocytosis of connexons to be recycled (Segretain & Falk, ; Laird, ; Farnsworth & Benninger, ).…”

Section: Discussionmentioning

confidence: 99%

“…Cx36 connexons, or functional channels, aggregate in the cellular membrane at tight junctions forming plaques, or gap junctions (Duffy et al 2002). While cAMP has been shown to increase gap junction coupling in Novikoff hepatoma cells (Paulson et al 2000) and smooth muscle cells (Begandt et al 2013), the mechanisms of cAMP regulation of Cx36 coupling in β-cells has not been directly studied. Changes in Cx36 turnover may reflect a number of regulatory mechanisms, including Cx36 gene expression, Cx36 trafficking to the membrane, recruitment and assembly of Cx36 into gap junction plaques, and endocytosis of connexons to be recycled (Segretain & Falk, 2004;Laird, 2006;.…”

Section: Regulation Of Gap Junction Couplingmentioning

confidence: 99%

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Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Farnsworth

Walter

Piscopio

et al. 2018

The Journal of Physiology

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Key points The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca2+ signalling and electrical coupling of the insulin producing β‐cells in the islet. We have previously shown that cytokines decrease β‐cell coupling and that compounds which increase cAMP can increase coupling. In both mouse and human islets exendin‐4, which increases cAMP, protected against cytokine‐induced decreases in coupling and in mouse islets preserved glucose‐stimulated calcium signalling by increasing connexin36 gap junction levels on the plasma membrane. Our data indicate that protein kinase A regulates β‐cell coupling through a fast mechanism, such as channel gating or membrane organization, while Epac2 regulates slower mechanisms of regulation, such as gap junction turnover. Increases in β‐cell coupling with exendin‐4 may protect against cytokine‐mediated β‐cell death as well as preserve insulin secretion dynamics during the development of diabetes. Abstract The pancreatic islets of Langerhans maintain glucose homeostasis. Insulin secretion from islet β‐cells is driven by glucose metabolism, depolarization of the cell membrane and an influx of calcium, which initiates the release of insulin. Gap junctions composed of connexin36 (Cx36) electrically couple β‐cells, regulating calcium signalling and insulin secretion dynamics. Cx36 coupling is decreased in pre‐diabetic mice, suggesting a role for altered coupling in diabetes. Our previous work has shown that pro‐inflammatory cytokines decrease Cx36 coupling and that compounds which increase cAMP can increase Cx36 coupling. The goal of this study was to determine if exendin‐4, which increases cAMP, can protect against cytokine‐induced decreases in Cx36 coupling and altered islet function. In both mouse and human islets, exendin‐4 protected against cytokine‐induced decreases in coupling and preserved glucose‐stimulated calcium signalling. Exendin‐4 also protected against protein kinase Cδ‐mediated decreases in Cx36 coupling. Exendin‐4 preserved coupling in mouse islets by preserving Cx36 levels on the plasma membrane. Exendin‐4 regulated Cx36 coupling via both protein kinase A (PKA)‐ and Epac2‐mediated mechanisms in cytokine‐treated islets. In mouse islets, modulating Epac2 had a greater impact in mediating Cx36 coupling, while in human islets modulating PKA had a greater impact on Cx36 coupling. Our data indicate that PKA regulates Cx36 coupling through a fast mechanism, such as channel gating, while Epac2 regulates slower mechanisms of regulation, such as Cx36 turnover in the membrane. Increases in Cx36 coupling with exendin‐4 may protect against cytokine‐mediated β‐cell dysfunction to insulin secretion dynamics during the development of diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Regulation Of Gap Junction Couplingmentioning

confidence: 99%

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Farnsworth

Walter

Piscopio

et al. 2018

The Journal of Physiology

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“…35 Chick chorioallantoic membrane vasculature was exposed for DIP increases the concentration of cytosolic cAMP which is believed to increase GJ coupling via different pathways such as elevated Cx trafficking, changes in phosphorylation status and increased Cx expression.…”

Section: Pharmacological Modulation Of Gap Junction Functionmentioning

confidence: 99%

“…DIP increases the concentration of cytosolic cAMP which is believed to increase GJ coupling via different pathways such as elevated Cx trafficking, changes in phosphorylation status and increased Cx expression. 35 Chick chorioallantoic membrane vasculature was exposed for…”

Section: Pharmacological Modulation Of Gap Junction Functionmentioning

confidence: 99%

Gap junctions regulate vessel diameter in chick chorioallantoic membrane vasculature by both tone‐dependent and structural mechanisms

et al. 2019

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Objective In this study, we examined the impact of gap junction blockade on chick chorioallantoic membrane microvessels. Methods Expression of Cx37, Cx40/42, and Cx43 in chick chorioallantoic membrane tissue was studied by PCR, Western blot, and confocal immunofluorescence microscopy. Vessel diameter changes occurring under gap junction blockade with carbenoxolone (175 µmol/L), palmitoleic acid (100 µmol/L), 43GAP27 (1 mmol/L) were analyzed by intravital microscopy. To analyze vascular tone, chick chorioallantoic membrane vessels were exposed to a vasodilator cocktail consisting of acetylcholine (10 μmol/L), adenosine (100 μmol/L), papaverine (200 μmol/L), and sodium nitroprusside (10 μmol/L). Results In chick chorioallantoic membrane lysates, Western blot analysis revealed the expression of Cx40 and Cx43. Immunofluorescence in intact chick chorioallantoic membrane vasculature showed only Cx43, limited to arterial vessel walls. Upon gap junction blockade (3 hours) arterial and venous diameters decreased to 0.50 ± 0.03 and 0.36 ± 0.06 (carbenoxolone), 0.72 ± 0.08 and 0.63 ± 0.15 (palmitoleic acid) and 0.77 ± 0.004 and 0.58 ± 0.05 (GAP27), relative to initial values. Initially, diameter decrease was dominated by increasing vascular tone. After 6 hours, however, vessel tone was reduced, suggesting structural network remodeling. Conclusions Our findings suggest a major role for connexins in mediating acute and chronic diameter changes in developing vascular networks.

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“…DPA is used as an antiplatelet agent, either alone or in combination with other pharmaceutical agents in order to reduce the risk of stroke incidents after a severe cardiovascular event, such as myocardial infarction [19,20]. Additionally, it can increase gap junction coupling in aortic endothelial and vascular smooth muscle cells [21,22]. One of the conclusions of these studies was that DPA is best utilized in sustained release forms of administration like microspheres.…”

Section: Introductionmentioning

confidence: 99%

Pcl/Peg Electrospun Fibers as Drug Carriers for the Controlled Delivery of Dipyridamole

Repanas¹,

Wf²,

O³

et al. 2015

J In Silico In Vitro Pharmacol

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Electrospinning is a versatile and diverse technology for the production of nano-and microfibers that can be used as a drug delivery system (DDS). The aim of this study was to create fibrous scaffolds from a mixture of polycaprolactone (PCL) and polyethylene glycol (PEG) and to evaluate the suitability of the fibers as DDS. Dipyridamole (DPA), an anti-thrombotic and anti-proliferative pharmaceutical agent, was used as a model drug. Two types of PEG with different chain length were used. The structural, mechanical and physicochemical characteristics of the fibers with and without DPA, were determined, and the release kinetics of DPA were studied. The obtained fibers loaded with DPA and with the higher molecular weight PEG were smooth and had an average diameter of 586.75 ± 204.79 nm and an average Young's modulus of 57.14 ± 4.35 MPa, whereas the tensile strain at break was 0.61 ±0.05 mm/mm and the ultimate tensile strength (UTS) was 16.79 ± 3.08 MPa. The cumulative release of DPA revealed two stages: an initial burst phenomenon followed by slower Fickian diffusion (release exponent n = 0.432).

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Biphasic increase of gap junction coupling induced by dipyridamole in the rat aortic A-10 vascular smooth muscle cell line

Cited by 9 publications

References 50 publications

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

Gap junctions regulate vessel diameter in chick chorioallantoic membrane vasculature by both tone‐dependent and structural mechanisms

Pcl/Peg Electrospun Fibers as Drug Carriers for the Controlled Delivery of Dipyridamole

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