Endothelial mitochondria as a possible target for potassium channel modulators

Pharmacological Reports 2006, 58, suppl., 89–95 ISSN 1734-1140

Copyright © 2006 by Institute of Pharmacology Polish Academy of Sciences

Review

Endothelial mitochondria as a possible target for potassium channel modulators Marta G³¹b1, Agnieszka £ojek2, Antoni Wrzosek1, Krzysztof Do³owy2, Adam Szewczyk1 1 Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Pasteura 3, PL 02-093 Warszawa, Poland 2

Department of Biophysics, Agriculture University SGGW, Nowoursynowska 159, PL 02-776 Warszawa, Poland

Correspondence: Adam Szewczyk, e-mail: [email protected]

Abstract: Variety of ion channels is present in plasma membrane of endothelial cells. These include the potassium channels such as Ca2+-activated K+ channels, inwardly rectifying K+ channels, voltage-dependent K+ channels and also ATP-regulated K+ channels. Due to an influence on the membrane potential they are important regulators of vascular tone by modulating endothelial calcium ions signaling and synthesis of vasodilating factors. Potassium channels in mitochondrial membranes of various tissues, similar to plasma membrane potassium channels, are described. Mitochondrial potassium channels such as ATP-regulated or large conductance Ca2+-activated and voltage gated channels are implicated in cytoprotective phenomenon in different tissues. In this paper we describe the pharmacological properties of mitochondrial potassium channels and discuss their role of as novel pharmacotherapeutic targets in endothelium. Key words: mitochondria, endothelial cells, potassium channel openers, diazoxide

Abbreviations: BKCa channel – large conductance Ca2+-activated potassium channel, BLM – black lipid membrane technique, ChTx – charybdotoxin, IbTx – iberiotoxin, EDHR – endothelium–derived hyperpolarizing factor, 5-HD – 5-hydroxydecanoic acid, KATP channel – ATP-regulated potassium channel, mitoBKCa channel – mitochondrial large conductance calcium-activated potassium channel, mitoKATP channel – mitochondrial ATP-regulated potassium channel, mitoKv1.3 channel – mitochondrial voltage gated potassium channel, NS1619 – 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]5-(trifluoromethyl)-2H-benzimidazole-2-one, PGI2 – prostacyclin, TNF-a – tumor necrosis factor a

Introduction The endothelium is the monolayer of cells that line the interior surface of blood vessels and plays an im-

portant role in the homeostasis of vascular function. The endothelial cells interact with other cells including lymphocytes, neutrophils, macrophages, platelets and smooth muscle cells. The endothelium is involved in many aspects of vascular biology, including vasoconstriction and vasodilation, atherosclerosis, angiogenesis, thrombosis, fibrinolysis, inflammation, and passage of materials into and out of the bloodstream, including transit of white blood cells [15]. There are also highly differentiated endothelial cells to perform specialized functions (e.g. unique endothelial structures include the renal glomerulus and the blood-brain barrier). The endothelium interacts with environment by synthesis and secretion of vasoactive substances (e.g nitric oxide (NO), endotheliumderived hyperpolarizing factor (EDHR)), direct contact with other cells, and via interactions with extracellular matrix through cell surface molecules. EndoPharmacological Reports, 2006, 57, suppl., 89–95

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thelial dysfunction often leads to atherosclerosis which is very common in patients with diabetes mellitus, hypertension or other chronic pathophysiological conditions. Increase in the intracellular calcium concentration is a signaling event leading to release of vasoactive factors such as NO, prostacyclin (PGI2), and epoxides of arachidonic acid as well as impacting the barrier function of these cells [1, 9, 25, 26, 31]. The favorable electrochemical gradient for Ca2+ entry is dependent on the membrane potential and an activity of potassium channels [1]. Hence, potassium channels play an important role in the regulation of vascular endothelium. Variety of ion channels is present in plasma membrane of endothelial cells. These includes the potassium channels such as Ca2+-activated K+ channels (BKCa channels), inwardly rectifying K+ channels (KIR channels), and also voltage-dependent K+ channels (KV channels). Endothelial potassium channels have been implicated in endothelium dependent vasodilation. It is due to setting the membrane potential leading to modulation endothelial calcium ions signaling and synthesis of vasodilating factors.

Potassium channels in plasma membrane of endothelial cells The endothelial cells express a diverse spectrum of potassium channels present in plasma membrane, including small (SKCa) and intermediate (IKCa) conductance Ca2+-activated K+ channels, KIR, ATP-regulated potassium channel (KATP), and KV channel. Both SKCa and IKCa channels are opened by endotheliumdependent vasodilators that increase endothelial cells intracellular Ca2+ causing membrane hyperpolarization that may be conducted through myoendothelial gap junctions to hyperpolarize and relax arteriolar vascular smooth muscle. KIR channels may serve to amplify SKCa and IKCa channels-induced hyperpolarization and allow active transmission of hyperpolarization along endothelial cells through gap junctions [36, 50]. Endothelial KATP channels have the potential to provide a mechanism for coupling blood flow to the metabolic requirements of the tissue [39]. It has been suggested that KV channels may participate in membrane potential oscillations and negative feedback regulation of membrane potential [22]. En-

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dothelial cell KIR channels may function as sensors for elevated extracellular K+ and provide a hyperpolarizing signal to alter vessel function [12]. Cultured vascular endothelial cells studies also suggest that KIR channels are involved in shear-stress-induced hyperpolarization of endothelial cells and their expression may be modulated by fluid shear [32, 37]. Vasoconstrictors such as angiotensin II, vasopressin, endothelin, and histamine have been reported to inhibit KIR channels in endothelial cells by a G-proteindependent mechanism [50]. Depending on the vessel and the species studied, sKCa, IKCa [36] or both channels mediate agonist-induced hyperpolarization of endothelial cells and play a major role in arteriolar dilation induced by endothelium-dependent vasodilators, such as acetylcholine, substance P, bradykinin, and histamine [50]. The hyperpolarization induced by Ca2+-triggered opening of these channels may be conducted along the endothelium via endothelial gap junctions and transmitted to smooth muscle cells through myoendothelial gap junctions leading to vasodilation [24, 56]. As noted above, the studies of vascular endothelial cells have also shown that this hyperpolarization increases the driving force for endothelial cell Ca2+ entry and autacoid production [50]. Mitochondria in endothelial cells

Mitochondria play a crucial role in cell energy homeostasis and function as main energy source. However, there is growing body of evidence that mitochondria in endothelial cells can also act as signaling organell [55]. Mitochondria are well known as a source of reactive oxygen species (ROS), especially of superoxide on complex I and III of respiratory chain, however, other source of ROS in mitochondria such as dehydrogenase are considered [38]. Reactive oxygen species are produced in endothelial cells under various conditions, for example when exposed to tumor necrosis factor a (TNF-a) [66] or reoxygenation after hypoxia and glucose depletion [11]. Mitochondria can also act as signaling organelles via regulation of calcium concentration within the cells, as they are important, besides endoplasmic reticulum, store of intracellular Ca2+ [67]. Mitochondrial ion channels

Energy generation within the cell is the fundamental role of mitochondria. Apart from this fundamental

Mitochondria and potassium channels in endothelial cells Marta G³âb et al.

role, mitochondria are involved in other complex processes such as apoptosis. Apoptosis of endothelial cells leads to such phenomena as an increased risk of thrombosis and it plays an important role in the progression of atherosclerosis [45]. The process of apoptosis triggered by many stimuli includes release of pro-apoptotic proteins, such as cytochrome c, from mitochondrial intermembrane space, which leads to caspase activation. This leak of pro-apoptotic key effector proteins is thought to be controlled by Bcl-2 family proteins [21, 43]. Recently, potassium transport through mitochondrial inner membrane was identified to trigger cytoprotection [8, 48, 51]. This transport is facilitated by ion channels similar to plasma membrane channels. Potassium ions control mitochondrial metabolism primarily due to regulation of matrix volume [29]. The basic pharmacological properties of mitochondrial potassium channels such as ATP-regulated potassium (mitoKATP) channel, large conductance Ca2+-activated potassium (mitoBKCa) channel were found to be similar to some of the potassium channels present in the plasma membrane of various cell types [65]. Recently, a margatoxinsensitive voltage gated Kv1.3 channel was identified in T lymphocytes mitochondria [62]. Interestingly, it was shown that Kv1.3 is present both in the plasma and mitochondrial membranes, despite lacking the N-terminal mitochondrial targeting sequence. Mitochondrial Kv1.3 channel may represent an important factor in the apoptotic signal transduction [62]. Mitochondrial ATP-regulated K+ channel

The mitoKATP channel was initially described in liver mitochondria [34]. Subsequently, it was also identified in heart [54], brain [3, 20], renal [10], skeletal muscle [19] and human T-lymphocyte mitochondria [13]. The activity of this channel is modulated by various nucleotides [54]. The molecular identity of the mitoKATP channel is presently unknown. Immunological studies revealed the existance of both pore forming Kir6.1 and Kir6.2 subunits in brain mitochondria [44]. It has also been hypothesized that a complex of five proteins (including succinate dehydrogenase) in the mitochondrial inner membrane is capable of transporting K+ with characteristics similar to those of the mitoKATP channel [2]. Similarly, molecular properties of the mitochondrial sulfonylurea receptor (mitoSUR) are also not clear. The use of the sulfonylurea derivative

[125I]glibenclamide leads to labeling of a 28 kDa protein in heart mitochondria [63]. A 64 kDa protein was labeled in brain mitochondria with the use of the fluorescent probe BODIPY-glibenclamide [3]. Activity of this channel is modulated by drugs known as potassium channel openers [23]. All of the potassium channel openers applied on mitochondria were previously used to activate plasma membrane ATP-regulated potassium channel but potassium channel openers such as diazoxide or (3R)-trans-4((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl2H-1-benzopyran-6-carbonitril monohydrochloride (BMS191095), are considered to be mitochondrial selective openers. Similarly, 5-hydroxydecanoic acid (5-HD) has some mitochondrial specificity as mitoKATP channel blocker. An important contribution to understanding the pharmacological properties of the mitoKATP channel come from the use of the techniques allowing single channel recording such as patch clamp or black lipid membranes (BLM) [4, 6, 13, 34, 49, 70]. The following pharmacological properties were described for mitoKATP channel: 1. The channel is blocked by ATP/Mg [6, 34, 35, 54, 70], 2. The ATP/Mg-inhibited channel is activated by the potassium channel opener diazoxide [27, 35] or BMS191095, 3. The channel is blocked by 5-HD [35, 49, 70] and by glibenclamide [6, 34, 35, 54], 4. The plasma membrane cardiac KATP channel blocker HMR1098 should be without effect on the channel activity [58, 70].

diazoxide cromakalim pinacidil BMS191095 RP66471 nicorandil P1075 isoflurane

inner mitochondrial membrane

matrix

+ K+

glibenclamide 5-hydroxydecanoic acid quinine N-ethylmaleimide

mitoKATP

-

Fig. 1. Pharmacological regulators of the mitochondrial ATP-

regulated potassium (mitoKATP) channel

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Some of the substances acting on mitoKATP channel show additional effect on isolated mitochondria. Diazoxide is known to inhibit mitochondrial succinate dehydrogenase [28] and induce uncoupling of mitochondria [33, 42]. Glibenclamide is also able to uncouple mitochondria at a high concentration [64] or to induce mitochondrial permeability transition [60]. Recently, it was reported that 5-HD is rapidly converted to 5-HD-CoA by mitochondrial fatty acyl-CoA synthetase and acts as a weak substrate or inhibitor of mitochondrial respiration [30, 46]. Hence, in some reports the existence of the mitoKATP channel in inner mitochondrial membrane is questioned [6, 14, 30, 53]. It is proposed that the pharmacological preconditioning by mitoKATP channel modulators may be related to partial inhibition of respiratory chain complexes [30, 41]. Mitochondrial large conductance calciumactivated potassium channel

A putative mitochondrial large conductance Ca2+-activated potassium channel (mitoBKCa channel) was originally described using patch-clamp technique in human glioma cell line LN229 [59]. This channel, with a conductance of 295 pS, was found to be stimulated by Ca2+ and blocked by charybdotoxin (ChTx). Later the presence of a channel with properties similar to the surface membrane calcium-activated K+ channel (stimulated by the potassium channel opener 1,3-Dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]5-trifluoromethyl)-2H-benzimidazol-2-one (NS1619) and blocked by ChTx, iberiotoxin (IbTx) and paxilline) was observed in patch-clamp recordings from mitoplasts of guinea pig ventricular cells [69]. It was reported that activation of cardiac mitoBKCa NS1619 (measured by flavoprotein oxidation) is amplified by 8-bromoadenosine-3’,5’-cyclic monophosphate and forskolin [57]. This observation may suggest that opening of mitoBKCa is modulated by cAMPdependent protein kinase. It should be mentioned, that the mitoBKCa channel may offer a novel link between cellular/mitochondrial calcium signaling and mitochondrial membrane potential-dependent reactions. Altered intramitochondrial calcium levels directly affect the potassium permeability of the mitochondrial inner membrane thus modulating the membrane potential. This type of interaction can modulate the efficiency of oxidative phosphorylation in a calcium-dependent manner. 92

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inner mitochondrial membrane

NS1619

matrix

+ K+ charybdotoxin iberiotoxin paxilline

mitoBKCa

-

Fig. 2. Pharmacological regulators of the mitochondrial large con-

ductance Ca2+- activated potassium (mitoBKCa) channel

Probably the mitochondrial channel has its ChTx/IbTx binding site close to the cytosolic compartment since those compounds as peptides cannot easily enter the mitochondrial matrix space. Consequently, the calcium binding site of the mitoBKCa channel is close to the matrix compartment (cf. orientation of the plasma membrane BKCa channel [68]). Similar to the mitochondrial ATP-regulated potassium channel, this novel potassium channel is expected to affect mitochondrial metabolism due to regulation of matrix volume [29]. In addition to this classical physiological effect of mitochondrial potassium transport, a pivotal role of mitochondrial potassium channels has been implicated in cardio- and neuroprotection [7, 48, 51]. It is therefore reasonable to expect a possible cytoprotective effect of mitoBKCa channel activation, probably in the presence of superoxide radicals [61]. Recently, it was shown that cardioprotective effects of estradiol include the activation of mitoBKCa channel in cardiac mitochondria [52]. Additionally, it was suggested that b1 subunit of BKCa channel is present in inner mitochondrial membrane and interacts with cytochrome c oxidase subunit I [52]. It has also been reported that two BKCa channel openers such as NS004 or NS1619, inhibit mitochondrial function in human glioma cells due to inhibition of the complex I of mitochondrial respiratory chain [18]. Recently, a channel opener NS1619 was shown to inhibit the function of isolated cardiac mitochondria in similar manner [40].

Mitochondria and potassium channels in endothelial cells Marta G³âb et al.

Mitochondrial potassium channels in endothelial mitochondria?

It is well established that endothelial dysfunction contributes to ischemia-reperfusion injury. This can be limited by the ischemic preconditioning. Mitochondrial potassium channels are involved in complex mechanism of ischemic preconditiong. Recently, it was shown that mitoKATP channel activation induced ischemic preconditiong of the endothelium in humans in vivo [5]. Probably ischemic preconditioning and potassium channel opener diazoxide protect endothelium in the mechanism involving attenuation of ROS level at reperfusion [47]. It was hypothesized that lidocaine and other amide local anesthetics may trigger the protection against endothelial cell injury (induced by inflammation) through activation of the mitoKATP channel [17]. The effects of amide local anesthetics (such as lidocaine), ester local anesthetics (such as tetracaine) on viability of human microvascular endothelial cells was studied after exposure to lipopolysacharide (LPS) in the absence or presence of the mitoKATP channel inhibitor 5-HD. Moreover, flavoprotein fluorescence was used to investigate the effects of these substances on potassium channel opener diazoxide-induced activation of the mitoKATP channels. Lidocaine attenuated the decrease of cell viability caused by LPS by around 60%. This protection was inhibited by 5-HD. Tetracaine was without effect on LPS-induced injury. It was concluded by authors that amide local anesthetic attenuated LPS-induced cell injury, in part, through activation of mitoKATP [17]. Interestingly, it was also shown that lidocaine protects endothelial and vascular smooth muscle cells against cytokine (such as TNF-a) induced injury [16].

Conclusion Variety of observations suggest that mitochondria contributes to cytoprotective phenomenon in various tissues. It seems that mitochondrial potassium channels such as ATP-regulated or Ca2+- activated, play the key role in these effects. Mitochondrial potassium channels are present in variety of cell types. This suggests that mitochondrial potassium channels present in endothelium may be involved in protective mecha-

nism of these cells. Hence, endothelial mitochondria may constitute an attractive target for potassium channels openers acting on mitoKATP channels and probably on mitoBKCa channels.

Acknowledgements:

This study was supported by the Ministry of Science and Higher Education grants PBZ-MIN-001/PO5/11 and N301 053 31/1676.

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Received:

September 29, 2006; in revised form: December 13, 2006

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