The Mechanism of Endothelium-Independent Relaxation Induced by the Wine Polyphenol Resveratrol in Human Internal Mammary Artery

Novakovic, Aleksandra; Gojkovic-Bukarica, Ljiljana; Perić, Miodrag; Nezic, Dusan; Djukanovic, Bosko; Marković-Lipkovski, Jasmina; Heinle, H.

doi:10.1254/jphs.fp0050863

Cited by 79 publications

(84 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By showing that, like glibenclamide, resveratrol can act as a blocker of the SUR1/K IR 6.2 channel, we have provided further evidence for analogies between both substances. In previous studies, a stimulatory effect of resveratrol on Ca 2ϩ -activated or voltage-gated K ϩ channels was reported, but no evidence for an effect on K ATP channels was obtained (45)(46)(47). Because the subunit composition of K ATP channels might be decisive in this respect, a systematic comparison of channels containing different SUR isoforms could be of future interest.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Hambrock

Franz

Hiller

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K ؉ channels (K ATP channels). SUR binds nucleotides and synthetic K ATP channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/ K IR 6.2 K ATP channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of K ATP channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic ␤-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research.Sulfonylurea receptors (SURs) 2 are members of the ATPbinding cassette protein family (subfamily C). SURs are known to be the important regulatory subunits of ATP-sensitive K ϩ channels (K ATP channels). These channels are heteromeric complexes composed of four SUR subunits that surround a central pore formed by four subunits from the K IR 6.x family. K ATP channels found in various tissues exhibit distinct physiological and pharmacological properties because of the combination of different subunit isoforms (reviewed in Ref. 1). In addition to two nucleotide-binding domains, SUR possesses binding sites for synthetic K ATP channel modulators. The binding sites for blockers and openers are different, but they are linked via complex allosteric interactions (2, 3).Because of their nucleotide sensitivity, K ATP channels couple the energy metabolism of a cell to the membrane potential. This is important in the pancreatic ␤-cell, in which closure of K ATP channels triggers insulin secretion via membrane depolarization in response to changes in blood glucose levels (4 -6). K ATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways...

show abstract

Section: Discussionmentioning

confidence: 99%

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Hambrock

Franz

Hiller

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…116 The same group repeated the study using endothelium-independent human internal mammary artery (HIMA) obtained from male patients undergoing coronary artery bypass surgery, and a similar conclusion was reached. 117 Resveratrol also inhibits the production of endogenous vasoconstrictors. In vascular smooth muscle cells (VSMCs) generation of oxidative stress induced endothelin-1 (ET-1) was inhibited by resveratrol.…”

Section: Effect On Vasorelaxationmentioning

confidence: 99%

Resveratrol: A multitargeted agent for age-associated chronic diseases

Harikumar¹,

Aggarwal²

2008

Cell Cycle

483

339

View full text Add to dashboard Cite

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g., NFκB, STAT3, HIF-1α, β-catenin and PPAR-γ), suppress the expression of antiapoptotic gene products (e.g., Bcl-2, Bcl-X L , XIAP and survivin), inhibit protein kinases (e.g., src, PI3K, JNK and AKT), induce antioxidant enzymes (e.g., catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

show abstract

“…Also, in different experimental models, resveratrol can activate adenylate cyclase and membrane-bound guanylyl cyclase and inhibit cGMP-specific phosphodiesterse-5 (13 -15). Previously, we have shown that resveratrol produces relaxation of the isolated human internal mammary artery and rat aorta by activation of margatoxin-sensitive voltage-dependent K + (K V ) channels located in the smooth muscle (7,16). In contrast, Orsini et al (17) suggested that resveratrol derivates inhibited K V channels in the F-11 neuroblastoma cells.…”

Section: Introductionmentioning

confidence: 99%

“…The resveratrol-induced vasorelaxation may either be endothelium-dependent (attenuated by L-NAME) or endothelium-independent (6,7,10). The mechanism of endothelium-independent vasorelaxation induced by resveratrol is uncertain.…”

Section: Introductionmentioning

confidence: 99%

A Role of Ion Channels in the Endothelium-Independent Relaxation of Rat Mesenteric Artery Induced by Resveratrol

et al. 2008

Self Cite

View full text Add to dashboard Cite

Abstract.Recently it has been suggested that resveratrol relaxes different isolated arteries. The present study addressed the question whether different ion channels are involved in the endothelium-independent mechanism of vasodilatation induced by resveratrol. For that purpose, we tested the action of resveratrol on the rat mesenteric artery without endothelium. Resveratrol induced concentration-dependent relaxation of rat mesenteric artery. Among the K + -channel blockers, 4-amynopiridine (4-AP) moderately antagonized the resveratrol-induced relaxation, while glibenclamide, tetraethylammonium chloride, charybdotoxin, margatoxin, and barium chloride did not inhibit resveratrol-induced vasorelaxation. In rings, precontracted with 100 mM K + , the relaxant responses to resveratrol were highly significantly shifted to the right compared to those obtained in rings precontracted with phenylephrine, but resveratrol-induced maximal relaxation was only slightly affected. In order to minimize the influence of K + channels and voltage-gated Ca 2+ channels (VGCCs) in vascular smooth muscle, the third contraction was made by 100 mM K + in the presence of nifedipine. The relaxant response to resveratrol was abolished. Thus, the mechanism of vasorelaxation induced by resveratrol probably involves activation of 4-AP-sensitive K + channels. Its ability to completely relax the mesenteric artery precontracted with K + -rich solution suggests that K + channel-independent mechanism(s) are involved in its vasorelaxant effect. It seems that interaction with VGCCs plays a part in this K + channel-independent effect of resveratrol.

show abstract

The Mechanism of Endothelium-Independent Relaxation Induced by the Wine Polyphenol Resveratrol in Human Internal Mammary Artery

Cited by 79 publications

References 26 publications

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Resveratrol: A multitargeted agent for age-associated chronic diseases

A Role of Ion Channels in the Endothelium-Independent Relaxation of Rat Mesenteric Artery Induced by Resveratrol

Contact Info

Product

Resources

About