Aims: Mitochondria are known to play a central role in adrenocortical steroidogenesis. Recently, hydrogen sulfide (H2S), a gaseous transmitter endogenously produced by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), has been found to improve mitochondrial function. The present study aimed at examining whether CBS and CSE are expressed in adrenal glands, and investigated the role of these enzymes in the maintenance of mitochondrial function and the production of glucocorticoids in adrenocortical cells. Results: Both CBS and CSE are present in murine adrenocortical cells and account for H2S generation in adrenal glands. Using a combination of both in vivo and in vitro approaches, we demonstrated that either CBS/CSE inhibitors or small interfering RNAs led to mitochondrial oxidative stress and dysfunction, which meanwhile resulted in blunted corticosterone responses to adrenocorticotropic hormone (ACTH). These effects were significantly attenuated by the treatment of H2S donor GYY4137. Lipopolysaccharide (LPS) also caused mitochondrial damage, thereby resulting in adrenal insufficiency. Moreover, LPS inhibited CBS/CSE expression and H2S production in adrenal glands, while H2S donor GYY4137 protected against LPS-induced mitochondrial damage and hyporesponsiveness to ACTH. Local suppression of CBS or CSE in adrenal glands significantly increased the mortality in endotoxemic mice, which was also improved by GYY4137. Innovation: The identification of endogenous H2S generation as critical regulators of adrenocortical responsiveness might result in the development of new therapeutic approaches for the treatment of relative adrenal insufficiency during sepsis. Conclusions: Endogenous H2S plays a critical role in the maintenance of mitochondrial function in the adrenal cortex, thereby resulting in an adequate adrenocortical response to ACTH. Antioxid. Redox Signal. 21, 2192–2207.
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References
1.
AbidiP, ZhangH, ZaidiSM, ShenWJ, Leers-SuchetaS, CortezY, HanJ, and AzharS. Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway. J Endocrinol, 198: 193–207, 2008.
2.
AnnaneD, SebilleV, TrocheG, RaphaelJC, GajdosP, and BellissantE. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA, 283: 1038–1045, 2000.
3.
BatzofinBM, SprungCL, and WeissYG. The use of steroids in the treatment of severe sepsis and septic shock. Best Pract Res Clin Endocrinol Metab, 25: 735–743, 2011.
4.
BollaertPE, FieuxF, CharpentierC, and LevyB. Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock. Shock, 19: 13–15, 2003.
5.
BornsteinSR. Predisposing factors for adrenal insufficiency. N Engl J Med, 360: 2328–2339, 2009.
6.
BurnettG, MarcotteP, and WalshC. Mechanism-based inactivation of pig heart L-alanine transaminase by L-propargylglycine. Half-site reactivity. J Biol Chem, 255: 3487–3491, 1980.
7.
BurryL, LittleA, HallettD, and MehtaS. Detection of critical illness-related corticosteroid insufficiency using 1 ug adrenocorticotropic hormone test. Shock, 39: 144–148, 2013.
8.
CaliendoG, CirinoG, SantagadaV, and WallaceJL. Synthesis and biological effects of hydrogen sulfide (H2S): development of H2S-releasing drugs as pharmaceuticals. J Med Chem, 53: 6275–6286, 2010.
9.
CalvertJW, CoetzeeWA, and LeferDJ. Novel insights into hydrogen sulfide—mediated cytoprotection. Antioxid Redox Signal, 12: 1203–1217, 2010.
DellingerRP, LevyMM, RhodesA, AnnaneD, GerlachH, OpalSM, SevranskyJE, SprungCL, DouglasIS, JaeschkeR, OsbornTM, NunnallyME, TownsendSR, ReinhartK, KleinpellRM, AngusDC, DeutschmanCS, MachadoFR, RubenfeldGD, WebbS, BealeRJ, VincentJL, and MorenoR. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med, 39: 165–228, 2013.
12.
Enriquez de Salamanca A and Garcia R. Response of rat fasciculata-reticularis cells in primary culture to bacterial lipopolysaccharide. Microbes Infect, 7: 1077–1086, 2005.
13.
FuM, ZhangW, WuL, YangG, LiH, and WangR. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc Natl Acad Sci U S A, 109: 2943–2948, 2012.
14.
GozlinskaB. Aminooxyacetic acid-induced accumulation of GABA enhances clonidine hypotension. Pol J Pharmacol, 46: 175–178, 1994.
15.
HuangXJ, ZhangHH, WangX, HuangLL, ZhangLY, YanCX, LiuY, and YuanZH. ROS mediated cytotoxicity of porcine adrenocortical cells induced by QdNOs derivatives in vitro. Chem Biol Interact, 185: 227–234, 2010.
16.
JefcoateC. High-flux mitochondrial cholesterol trafficking, a specialized function of the adrenal cortex. J Clin Invest, 110: 881–890, 2002.
17.
KanczkowskiW, ChatzigeorgiouA, SamusM, TranN, ZacharowskiK, ChavakisT, and BornsteinSR. Characterization of the LPS-induced inflammation of the adrenal gland in mice. Mol Cell Endocrinol, 371: 228–235, 2013.
18.
KimuraH. Hydrogen sulfide: from brain to gut. Antioxid Redox Signal, 12: 1111–1123, 2010.
19.
LiJ, UmarS, IorgaA, YounJY, WangY, Regitz-ZagrosekV, CaiH, and EghbaliM. Cardiac vulnerability toischemia/reperfusion injury drastically increases in late pregnancy. Basic Res Cardiol, 107: 271, 2012.
20.
Lipiner-FriedmanD, SprungCL, LaterrePF, WeissY, GoodmanSV, VogeserM, BriegelJ, KehD, SingerM, MorenoR, BellissantE, and AnnaneD. Adrenal function in sepsis: the retrospective Corticus cohort study. Crit Care Med, 35: 1012–1018, 2007.
21.
LiuS, ZhuX, LiuY, WangC, WangS, TangX, and NiX. Endotoxin tolerance of adrenal gland: attenuation of corticosterone production in response to lipopolysaccharide and adrenocorticotropic hormone. Crit Care Med, 39: 518–526, 2011.
22.
LuC, KavalierA, LukyanovE, and GrossSS. S-sulfhydration/desulfhydration and S-nitrosylation/denitrosylation: a common paradigm for gasotransmitter signaling by H2S and NO. Methods, 62: 177–181, 2013.
23.
MarikPE, PastoresSM, AnnaneD, MeduriGU, SprungCL, ArltW, KehD, BriegelJ, BeishuizenA, DimopoulouI, TsagarakisS, SingerM, ChrousosGP, ZalogaG, BokhariF, and VogeserM. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med, 36: 1937–1949, 2008.
24.
MesottenD, VanhorebeekI, and Van den BergheG. The altered adrenal axis and treatment with glucocorticoids during critical illness. Nat Clin Pract Endocrinol Metab, 4: 496–505, 2008.
25.
MillerWL and AuchusRJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev, 32: 81–151, 2011.
26.
MoodyBF and CalvertJW. Emergent role of gasotransmitters in ischemia-reperfusion injury. Med Gas Res, 1: 3, 2011.
27.
MurphyMP. How mitochondria produce reactive oxygen species. Biochem J, 417: 1–13, 2009.
28.
MuruganRS, PriyadarsiniRV, RamalingamK, HaraY, KarunagaranD, and NaginiS. Intrinsic apoptosis and NF-kappaB signaling are potential molecular targets for chemoprevention by black tea polyphenols in HepG2 cells in vitro and in a rat hepatocarcinogenesis model in vivo. Food Chem Toxicol, 48: 3281–3287, 2010.
29.
MustafaAK, GadallaMM, SenN, KimS, MuW, GaziSK, BarrowRK, YangG, WangR, and SnyderSH. H2S signals through protein S-sulfhydration. Sci Signal, 2: ra722009, 2009.
30.
NakaoA, SugimotoR, BilliarTR, and McCurryKR. Therapeutic antioxidant medical gas. J Clin Biochem Nutr, 44: 1–13, 2009.
31.
NearyN and NiemanL. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes, 17: 217–223, 2010.
32.
PapapetropoulosA, PyriochouA, AltaanyZ, YangG, MaraziotiA, ZhouZ, JeschkeMG, BranskiLK, HerndonDN, WangR, and SzaboC. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci U S A, 106: 21972–21977, 2009.
33.
PennaC, PerrelliMG, TullioF, AngottiC, CamporealeA, PoliV, and PagliaroP. Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE. Basic Res Cardiol, 108: 371, 2013.
34.
SabatiniDD and De RobertisED. Ultrastructural zonation of adrenocortex in the rat. J Biophys Biochem Cytol, 9: 105–119, 1961.
35.
SenN, PaulBD, GadallaMM, MustafaAK, SenT, XuR, KimS, and SnyderSH. Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions. Mol Cell, 45: 13–24, 2012.
SirauxV, De BackerD, YalavattiG, MelotC, GervyC, MockelJ, and VincentJL. Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests. Crit Care Med, 33: 2479–2486, 2005.
38.
SkovgaardN, GouliaevA, AallingM, and SimonsenU. The role of endogenous H2S in cardiovascular physiology. Curr Pharm Biotechnol, 12: 1385–1393, 2011.
39.
SoutschekJ, AkincA, BramlageB, CharisseK, ConstienR, DonoghueM, ElbashirS, GeickA, HadwigerP, HarborthJ, JohnM, KesavanV, LavineG, PandeyRK, RacieT, RajeevKG, RöhlI, ToudjarskaI, WangG, WuschkoS, BumcrotD, KotelianskyV, LimmerS, ManoharanM, and VornlocherHP. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature, 432: 173–178, 2004.
40.
SunJ, MorganM, ShenRF, SteenbergenC, and MurphyE. Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport. Circ Res, 101: 1155–1163, 2007.
41.
TaitSW and GreenDR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol, 11: 621–632, 2010.
42.
TanizawaK. Production of H2S by 3-mercaptopyruvate sulphurtransferase. J Biochem, 149: 357–359, 2011.
43.
TengH, WuB, ZhaoK, YangG, WuL, and WangR. Oxygen-sensitive mitochondrial accumulation of cystathionine beta-synthase mediated by Lon protease. Proc Natl Acad Sci U S A, 110: 12679–12684, 2013.
44.
TruongDH, EghbalMA, HindmarshW, RothSH, and O'BrienPJ. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab Rev, 38: 733–744, 2006.
45.
VenkateshB and CohenJ. Adrenocortical (dys)function in septic shock—a sick euadrenal state. Best Pract Res Clin Endocrinol Metab, 25: 719–733, 2011.
46.
VincentAM, KatoK, McLeanLL, SoulesME, and FeldmanEL. Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. Antioxid Redox Signal, 11: 425–438, 2009.
47.
WagnerCA. Hydrogen sulfide: a new gaseous signal molecule and blood pressure regulator. J Nephrol, 22: 173–176, 2009.
48.
WangC and YouleRJ. The role of mitochondria in apoptosis. Annu Rev Genet, 43: 95–118, 2009.
49.
WangZ, CaiF, ChenX, LuoM, HuL, and LuY. The role of mitochondria-derived reactive oxygen species in hyperthermia-induced platelet apoptosis. PLoS One, 8: e75044, 2013.
50.
WhiteheadKA, LangerR, and AndersonDG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov, 8: 129–138, 2009.
51.
WhitemanM, ArmstrongJS, ChuSH, Jia-LingS, WongBS, CheungNS, HalliwellB, and MoorePK. The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’?. J Neurochem, 90: 765–768, 2004.
52.
WhitemanM, Le TrionnaireS, ChopraM, FoxB, and WhatmoreJ. Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Clin Sci (Lond), 121: 459–488, 2011.
WuPP, LiuKC, HuangWW, MaCY, LinH, YangJS, and ChungJG. Triptolide induces apoptosis in human adrenal cancer NCI-H295 cells through a mitochondrial-dependent pathway. Oncol Rep, 25: 551–557, 2011.
55.
YangG, ZhaoK, JuY, ManiS, CaoQ, PuukilaS, KhaperN, WuL, and WangR. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal, 18: 1906–1919, 2013.
56.
YuanY, ChenY, ZhangP, HuangS, ZhuC, DingG, LiuB, YangT, and ZhangA. Mitochondrial dysfunction accounts for aldosterone-induced epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells. Free Radic Biol Med, 53: 30–43, 2012.
57.
ZhuX, TangZ, CongB, DuJ, WangC, WangL, NiX, and LuJ. Estrogens increase cystathionine-gamma-lyase expression and decrease inflammation and oxidative stress in the myocardium of ovariectomized rats. Menopause, 20: 1084–1091, 2013.
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