Restricted accessResearch articleFirst published online 2015-07
Hydrogen Sulfide Targets the Cys320/Cys529 Motif in Kv4.2 to Inhibit the I to Potassium Channels in Cardiomyocytes and Regularizes Fatal Arrhythmia in Myocardial Infarction
Aims: The mechanisms underlying numerous biological roles of hydrogen sulfide (H2S) remain largely unknown. We have previously reported an inhibitory role of H2S in the L-type calcium channels in cardiomyocytes. This prompts us to examine the mechanisms underlying the potential regulation of H2S on the ion channels. Results: H2S showed a novel inhibitory effect on Ito potassium channels, and this effect was blocked by mutation at the Cys320 and/or Cys529 residues of the Kv4.2 subunit. H2S broke the disulfide bridge between a pair of oxidized cysteine residues; however, it did not modify single cysteine residues. H2S extended action potential duration in epicardial myocytes and regularized fatal arrhythmia in a rat model of myocardial infarction. H2S treatment significantly increased survival by ∼1.4-fold in the critical 2-h time window after myocardial infarction with a protection against ventricular premature beats and fatal arrhythmia. However, H2S did not change the function of other ion channels, including IK1 and INa. Innovation and Conclusion: H2S targets the Cys320/Cys529 motif in Kv4.2 to regulate the Ito potassium channels. H2S also shows a potent regularizing effect against fatal arrhythmia in a rat model of myocardial infarction. The study provides the first piece of evidence for the role of H2S in regulating Ito potassium channels and also the specific motif in an ion channel labile for H2S regulation. Antioxid. Redox Signal. 23, 129–147.
Get full access to this article
View all access options for this article.
References
1.
AngeliniP. Sudden cardiac death: do we know what we are talking about?. Circulation, 105: E182–E182, 2002.
2.
BazzaniC, MioniC, FerrazzaG, CainazzoMM, BertoliniA, and GuariniS. Involvement of the central nervous system in the protective effect of melanocortins in myocardial ischemia/reperfusion injury. Resuscitation, 52: 109–115, 2002.
3.
CaiWJ, WangMJ, MoorePK, JinHM, YaoT, and ZhuYC. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res, 76: 29–40, 2007.
4.
CannonCP, GibsonCM, LambrewCT, ShoultzDA, LevyD, FrenchWJ, GoreJM, WeaverWD, RogersWJ, and TiefenbrunnAJ. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA, 283: 2941–2947, 2000.
5.
CarmelietE. Function and pharmacology of the potassium channels in the heart and vessels. Arch Mal Coeur Vaiss, 85: 465–471, 1992.
6.
CarmelietE. K+ channels and control of ventricular repolarization in the heart. Fundam Clin Pharmacol, 7: 19–28, 1993.
7.
CatterallW. Voltage-dependent gating of sodium channels: correlating structure and function. Trends Neurosci, 9: 7–10, 1986.
8.
ChenL, XuY, LiW, WuH, LuoZ, LiX, HuangF, YoungC, LiuZ, and ZhouS. The novel compound liguzinediol exerts positive inotropic effects in isolated rat heart via sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism. Life Sci, 91: 402–408, 2012.
9.
ChengJH and KodamaI. Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin, 25: 137–145, 2004.
10.
ChikharevVN, Mal'tsevVA, and RozenshtraukhLV. Lidocaine action on the ion currents of normal and depolarized myocardial fibers in membrane potential fixation. Biull Vsesoiuznogo Kardiol Nauchn Tsentra AMN SSSR, 4: 58–66, 1981.
11.
CurtisMJ and WalkerMJ. Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischemia. Cardiovasc Res, 22: 656–665, 1988.
12.
DhamoonAS and JalifeJ. The inward rectifier current (Ik1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm, 2: 316–324, 2005.
13.
GelpiRJ, MoscaSM, RinaldiGJ, KosoglovA, and CingolaniHE. Effect of calcium antagonism on contractile behavior of canine hearts. Am J Physiol, 244: H378–H386, 1983.
14.
GiudicessiJR and AckermanMJ. Potassium-channel mutations and cardiac arrhythmias-diagnosis and therapy. Nat Rev Cardiol, 9: 319–332, 2012.
15.
HoeferIE. Something is rotten in the state of angiogenesis–H2S as gaseous stimulator of angiogenesis. Cardiovasc Res, 76: 1–2, 2007.
16.
HondeghemLM and KatzungBG. Unifying molecular model for interaction of antiarrhythmic drugs with cardiac sodium channels: application to quinidine and lidocaine. Pro West Pharmacol Soc, 20: 253–256, 1977.
17.
HutterOF and NobleD. Rectifying properties of heart muscle. Nature, 188: 495, 1960.
18.
Ion channels in the cardiovascular system. Science. 257: 271–273,. 1992.
19.
IshiiK, TairaN, and YanagisawaT. Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle. Br J Pharmacol, 84: 577–584, 1985.
20.
Jackson-WeaverO, ParedesDA, Gonzalez BoscLV, WalkerBR, and KanagyNL. Intermittent hypoxia in rats increases myogenic tone through loss of hydrogen sulfide activation of large-conductance Ca2+-activated potassium channels. Circ Res, 108: 1439–1447, 2011.
21.
JohnsonCC and MinerPF. The occurrence of arrhythmias in acute myocardial infarctions. Dis Chest, 33: 414–422, 1958.
22.
KhodorovaA, MeissnerK, LeesonS, and StrichartzGR. Lidocaine selectively blocks abnormal impulses arising from noninactivating Na+ channels. Muscle Nerve, 24: 634–647, 2001.
23.
KondoK, BhushanS, KingAL, PrabhuSD, HamidT, KoenigS, MuroharaT, PredmoreBL, GojonGSr., GojonGJr., WangR, KarusulaN, NicholsonCK, CalvertJW, and LeferDJ. H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation, 127: 1116–1127, 2013.
24.
LiL, RoseP, MoorePK, and ChoA. Hydrogen sulfide and cell signaling. Annu Rev Pharmacol and Toxicol, 51: 169–187, 2011.
OdohertyM, TaylerDI, QuinnE, VincentR, and ChamberlainDA. 500 patients with myocardial-infarction monitored within one hour of symptoms. Br Med J, 286: 1405–1408, 1983.
29.
OkuboK, TakahashiT, SekiguchiF, KanaokaD, MatsunamiM, OhkuboT, YamazakiJ, FukushimaN, YoshidaS, and KawabataA. Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. Neuroscience, 188: 148–156, 2011.
30.
PolhemusDJ, KondoK, BhushanS, BirSC, KevilCG, MuroharaT, LeferDJ, and CalvertJW. Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail, 6: 1077–1086, 2013.
31.
PriebeL and BeuckelmannDJ. Simulation study of cellular electric properties in heart failure. Circ Res, 82: 1206–1223, 1998.
32.
RadickeS, VaqueroM, CaballeroR, GomezR, NunezL, TamargoJ, RavensU, WettwerE, and DelponE. Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels. Br J Pharmacol, 154: 774–786, 2008.
33.
RosequistCC. Current standards and guidelines for cardiopulmonary-resuscitation and emergency cardiac care. Heart Lung, 16: 408–418, 1987.
34.
ShihHT. Anatomy of the action-potential in the heart. Tex Heart Inst J, 21: 30–41, 1994.
35.
StreeterE, HartJ, and BadoerE. An investigation of the mechanisms of hydrogen sulfide-induced vasorelaxation in rat middle cerebral arteries. Naunyn Schmiedebergs Arch Pharmacol, 385: 991–1002, 2012.
36.
SunX and WangHS. Role of the transient outward current (Ito) in shaping canine ventricular action potential—a dynamic clamp study. J Physiol, 564: 411–419, 2005.
37.
SunYG, CaoYX, WangWW, MaSF, YaoT, and ZhuYC. Hydrogen sulphide is an inhibitor of L-type calcium channels and mechanical contraction in rat cardiomyocytes. Cardiovasc Res, 79: 632–641, 2008.
38.
TamargoJ, CaballeroR, GomezR, ValenzuelaC, and DelponE. Pharmacology of cardiac potassium channels. Cardiovasc Res, 62: 9–33, 2004.
39.
TaoBB, LiuSY, ZhangCC, FuW, CaiWJ, WangY, ShenQ, WangMJ, ChenY, ZhangLJ, ZhuYZ, and ZhuYC. VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel cys1045-cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells. Antioxid Redox Signal, 19: 448–464, 2013.
40.
TianXY, WongWT, SayedN, LuoJ, TsangSY, BianZX, LuY, CheangWS, YaoX, ChenZY, and HuangY. NaHS relaxes rat cerebral artery in vitro via inhibition of L-type voltage-sensitive Ca2+ channel. Pharmacol Res, 65: 239–246, 2012.
41.
WeidmannS. The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system. J Physiol, 127: 213–224, 1955.
42.
YanGX, JoshiA, GuoD, HlaingT, MartinJ, XuX, and KoweyPR. Phase 2 reentry as a trigger to initiate ventricular fibrillation during early acute myocardial ischemia. Circulation, 110: 1036–1041, 2004.
43.
YaoLL, HuangXW, WangYG, CaoYX, ZhangCC, and ZhuYC. Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3 beta-dependent opening of mPTP. Am J Physiol Heart Circ Physiol, 298: H1310–H1319, 2010.
44.
ZhaoW, ZhangJ, LuY, and WangR. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J, 20: 6008–6016, 2001.
45.
ZhengZJ, CroftJB, GilesWH, and MensahGA. Sudden cardiac death in the United States, 1989 to 1998. Circulation, 104: 2158–2163, 2001.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
