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Age-related fibrosis is attenuated by aerobic exercise; however, little is known concerning the underlying molecular mechanism. To address this question, aged rats were given moderate-intensity exercise for 12 weeks. After exercise in aged rats, hydrogen sulfide levels in plasma and heart increased 39.8% and 90.9%, respectively. Exercise upregulated expression of cystathionine [gamma]-lyase and 3-mercaptopyruvate sulfurtransferase in heart of aged rats. Furthermore, aged rats were given moderate-intensity exercise for 12 weeks or treated with NaHS (intraperitoneal injection of 0.1 mL/kg per day of 0.28 mol/L NaHS). After exercise in aged rats, Masson-trichrome staining area decreased 34.8% and myocardial hydroxyproline levels decreased 29.6%. Exercise downregulated expression of collagen-I and [alpha]-smooth muscle actin in heart of aged rats. Exercise in aged rats reduced malondialdehyde levels in plasma and heart and 3-nitrotyrosine in heart. Exercise in aged rats reduced mRNA and protein expression of C/EBP homologous protein, glucose regulated protein 78, and X-box protein 1. Exercise also reduced mRNA and protein expression of interleukin 6 and monocyte chemotactic protein 1and suppressed activation of c-Jun N-terminal kinase in aging heart. Similar effects were demonstrated in aged rats treated with NaHS. Collectively, exercise restored bioavailability of hydrogen sulfide in the heart of aged rats, which partly explained the benefits of exercise against myocardial fibrosis of aged population. Key words: exercise training, fibrosis, heart, aging. La fibrose liee a l'age s'attenue avec l'exercice physique aerobie; cependant, on sait peu de choses des modes d'action moleculaires sous-jacents. Pour aborder cette question, nous avons soumis des rats ages a un exercice physique d'intensite moderee pendant 12 semaines. Apres l'exercice physique, nous avons observe chez les rats ages une augmentation des taux de sulfure d'hydrogene de 39,8 % dans le plasma et de 90,9 % dans le coeur. L'exercice physique entrainait une regulation a la hausse de l'expression de la cystathionine [gamma]-lyase et de la 3-mercaptopyruvate sulfurtransferase dans le coeur des rats ages. De plus, nous avons soumis les rats ages a un exercice physique d'intensite moderee pendant 12 semaines ou a l'administration de NaHS (injection intraperitoneale quotidienne de 0,1 mL/kg de NaHS a 0,28 mol/L). Apres l'exercice physique, nous avons observe chez les rats ages que la surface coloree au trichrome de Masson diminuait de 34,8 %, alors que les taux d'hydroxyproline myocardique diminuaient de 29,6 %. L'exercice physique entrainait une regulation a la baisse de l'expression du collagene I et de l'actine a du muscle lisse dans le coeur des rats ages. Chez les rats ages, l'exercice physique permettait de faire diminuer les taux de malondialdehyde dans le plasma et le coeur, ainsi que les taux de 3-nitrotyrosine dans le coeur. Chez les rats ages, l'exercice physique entrainait une diminution de l'expression en proteines et en ARNm de la proteine homologue C/EBP, de la proteine 78 regulee par le glucose et de la proteine 1 liant la boite X. L'exercice physique entrainait aussi une diminution de l'expression en proteines et en ARNm pour l'interleukine 6 et la proteine 1 chimiotactique des monocytes, avec une inhibition de l'activation de la kinase c-jun N terminale dans le coeur vieillissant. Nous avons montre des effets similaires avec l'administration de NaHS chez les rats ages. Collectivement, l'exercice physique a permis de retablir la biodisponibilite du sulfure d'hydrogene dans le coeur des rats ages, ce qui pourrait s'expliquer en partie par les bienfaits de l'exercice physique contre la fibrose myocardique dans la population agee. [Traduit par la Redaction] Mots-cles : entrainement par l'exercice physique, fibrose, coeur, vieillissement., Introduction Aging is an inevitable trend of the world's population, and it is of central importance as a dominant risk factor for the development of cardiovascular diseases, which account for [...]

Spontaneously hypertensive rats (SHR) display autonomic imbalance and abnormal body temperature (Tb) adjustments. Hydrogen sulfide ([H.sub.2]S) modulates hypoxia-induced hypothermia, but its role in SHR thermoregulation is unknown. We tested the hypothesis that SHR display peculiar thermoregulatory response to hypoxia and that endogenous [H.sub.2]S overproduced in the caudal nucleus of the solitary tract (NTS) of SHR modulates this response. SHR and Wistar rats were microinjected into the fourth ventricle with aminooxyacetate (AOA, [H.sub.2]S-synthezing enzyme inhibitor) or sodium sulfide ([Na.sub.2]S, [H.sub.2]S donor) and exposed to normoxia (21% inspired [O.sub.2]) or hypoxia (10% inspired [O.sub.2], 30 min). Tb was continuously measured, and [H.sub.2]S production rate was assessed in caudal NTS homogenates. In both groups, AOA, [Na.sub.2]S, or saline (i.e., control; 1 µL) did not affect euthermia. Hypoxia caused similar decreases in Tb in both groups. AOA presented a longer latency to potentiate hypoxic hypothermia in SHR. Caudal NTS [H.sub.2]S production rate was higher in SHR. We suggest that increased bioavailability of [H.sub.2]S in the caudal NTS of SHR enables the adequate modulation of excitability of peripheral chemoreceptor-activated NTS neurons that ultimately induce suppression of brown adipose tissue thermogenesis, thus accounting for the normal hypoxic hypothermia. Key words: hypoxia, nucleus of the solitary tract, NTS, anapyrexia, SHR, aminooxyacetate, cystathionine beta-synthase, brainstem, body temperature, thermoregulation. Chez le rat SHR (spontanement hypertendu), on observe un desequilibre autonome ainsi que des ajustements anormaux de la temperature corporelle (Tc). Le sulfure d'hydrogene ([H.sub.2]S) module l'hypothermie provoquee par l'hypoxie, mais son role dans la thermoregulation est inconnu chez le rat SHR. Nous avons teste l'hypothese selon laquelle le rat SHR reagit a l'hypoxie par une reponse thermoregulatrice particuliere, et qu'elle serait chez lui modulee par la surproduction de [H.sub.2]S endogene dans le noyau caude du tractus solitaire. Chez des rats SHR et Wistar, nous avons procede a la micro-injection d'aminooxyacetate (AOA, une enzyme inhibitrice de la synthese de [H.sub.2]S) ou de sulfure de sodium ([Na.sub.2]S, un donneur de [H.sub.2]S) dans le IVe ventricule et nous avons expose les animaux a la normoxie (a µL % d'[O.sub.2] inspire) ou a l'hypoxie (a 10 % d'[O.sub.2] inspire pendant 30 min). Nous avons mesure la Tc en continu et evalue le taux de production de [H.sub.2]S dans des homogenats de noyau caude du tractus solitaire. Dans les deux groupes, ni l'AOA, ni le [Na.sub.2]S, ni le vehicule (1 pL de solution saline) n'ont affecte l'euthermie. L'hypoxie a entraine un abaissement similaire de la Tc dans les deux groupes. Nous avons observe avec l'AOA une plus longue latence precedant la potentialisation de l'hypothermie hypoxique chez le rat SHR. Le taux de production de [H.sub.2]S dans le noyau caude du tractus solitaire etait aussi plus eleve chez le rat SHR. Ces resultats laissent penser que chez le rat SHR l'augmentation de la biodisponibilite du [H.sub.2]S dans le noyau caude du tractus solitaire permet la modulation adequate de l'excitabilite des neurones du noyau du tractus solitaire actives par les chimiorecepteurs peripheriques qui finit par annihiler la thermogenese par le tissu adipeux brun, ce qui explique l'hypothermie hypoxique normale. [Traduit par la Redaction] Mots-cles: hypoxie, noyau du tractus solitaire, anapyrexie, rat spontanement hypertendu, aminooxyacetate, cystathionine beta-synthase, tronc cerebral, temperature corporelle, thermoregulation., Introduction Hypoxia causes a number of compensatory responses to maintain oxygen supply to tissues and reduce oxygen consumption when oxygen availability is reduced. During hypoxia, ventilatory and cardiovascular responses are [...]

Hydrogen sulfide ([H.sub.2]S) is synthesized from L-cysteine by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), and is enzymatically metabolized in mitochondria by sulfide:quinone oxidoreductase (SQR). Recent studies have indicated that [H.sub.2]S is synthesized by CSE in perivascular adipose tissue (PVAT), and is responsible for the anticontractile effect of PVAT on adjacent vessels. The lipophilic statin atorvastatin increases PVAT-derived [H.sub.2]S by suppressing its mitochondrial oxidation; the effect that results from statin-induced depletion of ubiquinone. Experimental obesity induced by a highly palatable diet has a time-dependent effect on [H.sub.2]S in PVAT. Adipose tissue hypoxia suppresses [H.sub.2]S oxidation and increases its level in short-term obesity not associated with insulin resistance. In contrast, in long-term obesity, insulin resistance and (or) hyperinsulinemia result in the down-regulation of CSE and [H.sub.2]S deficiency, which is corrected by treatment with the insulin sensitizer rosiglitazone. In addition, cannabinoid CB1 receptor agonist administered for 2 weeks increases [H.sub.2]S by impairing mitochondria biogenesis. This indicates that the rate of mitochondrial [H.sub.2]S oxidation plays an important role in the regulation of [H.sub.2]S level in PVAT. Up-regulation of [H.sub.2]S signaling in short-term obesity and (or) by elevated endocannabinoids may be a compensatory mechanism that maintains vascular tone, despite endothelial dysfunction. Key words: hydrogen sulfide, perivascular adipose tissue, obesity, metabolic syndrome, arterial hypertension, vascular tone, insulin sensitivity, hypoxia, endocannabinoids. Le sulfure d'hydrogene ([H.sub.2]S) est synthetise a partir de la L-cysteine par la cystathionine β-synthase (CBS) ou la cystathionine γ-lyase (CSE), et il est metabolise de facon enzymatique dans la mitochondrie par la sulfide:quinone oxydoreductase (SQR). Des etudes recentes indiquent que le [H.sub.2]S est synthetise par la CSE dans le tissu adipeux perivasculaire (TAPV) et qu'il est responsable de l'effet anti-constricteur du TAPV sur les vaisseaux adjacents. L'atorvastatine, une statine lipophile, accroit le niveau de [H.sub.2]S derive du TAPV en supprimant son oxydation mitochondriale, consequence de la depletion en ubiquinone induite par la statine. L'obesite experimentale induite par une diete hautement palatable exerce un effet sur le [H.sub.2]S dans le TAPV en fonction du temps. L'hypoxie du tissu adipeux supprime l'oxydation du [H.sub.2]S et ses niveaux sont accrus dans l'obesite al court terme non associee a la resistance a l'insuline. Au contraire, dans l'obesite a long terme, la resistance a l'insuline et (ou) l'hyperinsulinemie resultent en une regulation a la baisse de la CSE et en une deficience en [H.sub.2]S, ce qui peut etre corrige par un traitement avec un sensibilisateur a l'insuline, le rosiglitazone. En outre, un agoniste du recepteur des cannabinoides CB1 administre pendant 2 semaines augmente le [H.sub.2]S en alterant la biogenese mitochondriale. Ces donnees indiquent que le taux d'oxydation mitochondriale de [H.sub.2]S joue un role important dans la regulation du niveau de [H.sub.2]S dans le TAPV. La regulation a la hausse de la signalisation du [H.sub.2]S dans l'obesite a court terme et (ou) lors de l'elevation des niveaux d'endocannabinoides peut constituer un mecanisme compensatoire qui maintien le tonus vasculaire malgre la dysfonction endotheliale. [Traduit par la Redaction] Mots-cles: sulfure d'hydrogene, tissu adipeux perivasculaire, obesite, syndrome metabolique, hypertension arterielle, tonus vasculaire, hypoxie, endocannabinoides., Introduction Perivascular adipose tissue (PVAT) surrounds most of the large (conduit) and medium-size (resistance) arteries and also some veins. PVAT is not a passive component of the vascular wall, or [...]

Hydrogen sulfide ([H.sub.2]S), an endogenous gaseous mediator, produces both vasorelaxation and vasoconstriction at different concentrations. We found in the present study that NaHS, an [H.sub.2]S donor, produced stronger vasorelaxant and weaker vasoconstrictive effects in HEPES solution compared with those achieved in Krebs solution. We further screened the buffer components and found that bicarbonate (HC[O.sup.-.sub.3]) was the ion to influence the effect of [H.sub.2]S. After examining the vasorelaxant effects of acetylcholine, a vasodilator by releasing nitric oxide, and isoprenaline, a [beta]-adrenoceptor agonist, in HEPES and Krebs buffers, we found the HC[O.sup.-.sub.3]-dependent effect was specific to [H.sub.2]S. Blockade of anion exchanger-2 activity with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) or with HC[O.sup.-.sub.3]-free solution abolished the vasoconstrictive effect of NaHS. Moreover, NaHS decreased nitric oxide level in the rat aorta in HC[O.sup.-.sub.3]-containing buffer, but this effect was abolished by HC[O.sup.-.sub.3]-free buffer or DIDS. In summary, we found for the first time that [H.sub.2]S stimulates anion exchanger to transport extracellular HC[O.sup.-.sub.3] in exchange for intracellular superoxide anions, which may further inactivate nitric oxide and induces vasoconstriction. anion exchanger; superoxide anions doi: 10.1152/ajpcell.00105.2010.

Systemic vascular resistance ([R.sub.sys]) of freshwater turtles increases substantially during anoxia, but the underlying mechanisms are not fully understood. We investigated whether hydrogen sulfide ([H.sub.2]S), an endogenously produced metabolite believed to be an [O.sub.2] sensor/ transducer of vasomotor tone, contributes to the increased [R.sub.sys] of anoxic red-eared slider turtles (Trachemys scripta). Vascular infusion of the [H.sub.2]S donor Naris in anesthetized turtles at 21[degrees]C and fully recovered normoxic turtles at 5[degrees]C and 21[degrees]C revealed [H.sub.2]S to be a potent vasoconstrictor of the systemic circulation. Likewise, wire myography of isolated turtle mesenteric and pulmonary arteries demonstrated [H.sub.2]S to mediate an anoxia-induced constriction. Intriguingly, however, Naris did not exert vasoconstrictory effects during anoxia (6 h at 21[degrees]C; 14 days at 5[degrees]C) when plasma [H.sub.2]S concentration, estimated from the colorimetric measurement of plasma acid-labile sulfide concentration, likely increased by ~3-and 4-fold during anoxia at 21[degrees]C, and 5[degrees]C, respectively. Yet, blockade of endogenous [H.sub.2]S production by DL-propargylglycine or hydroxylamine (0.44 mmol/kg) partially reversed the decreased systemic conductance ([G.sub.sys]) exhibited by 5[degrees]C anoxic turtles. These findings suggest that the signal transduction pathway of [H.sub.2]S-mediated vasoactivity is either maximally activated in the systemic circulation of anoxic turtles and/or that it is oxygen dependent. red-eared slider; anoxia; temperature; cardiovascular; systemic resistance; pulmonary resistance; blood pressure; heart doi: 10.1152/ajpregu.00521.2009.

The effect of the presence of sulfide on the survival of benthic organisms under hypoxia was tested using a meta-analysis of published experimental results evaluating the effects of the presence of hydrogen sulfide on the median survival time of benthic macrofauna under hypoxia. The meta-analysis confirmed that survival times under hypoxia are reduced by an average of 30% in marine benthic communities exposed to hydrogen sulfide. The effect of sulfide on survival was higher for egg forms than for juvenile or adult stages. The aggravation of the negative effects of spreading hypoxia in the presence of sulfide suggests that the threats derived from hypoxia to marine biodiversity are greater than anticipated on the basis of the direct effects of low oxygen concentration alone. doi: 10.4319/lo.2010.55.3.1075

Reactive oxygen and nitrogen species (ROS and RNS, respectively) generate nitrotyrosine and activate latent resident myocardial matrix metalloproteinases (MMPs). Although in chronic heart failure (CHF) there is robust increase in ROS, RNS, and MMP activation, recent data suggest that hydrogen sulfide ([H.sub.2]S, a strong antioxidant gas) is cardioprotective. However, the role of [H.sub.2]S in mitigating oxidative and proteolytic stresses in cardiac remodeling/apoptosis in CHF was unclear. To test the hypothesis that [H.sub.2]S ameliorated cardiac apoptosis and fibrosis by decreasing oxidative and proteolytic stresses, arteriovenous fistula (AVF) was created in wild-type (C57BL/6J) mice. The hearts were analyzed at 0, 2, and 6 wk after AVF. To reverse the remodeling, AVF mice were treated with NariS (an H2S donor, 30 [micro]mol/l in drinking water) at 8 and 10 wk. The levels of MMPs were measured by gelatin-gel zymography. The levels of nitrotyrosine, tissue inhibitors of metalloproteinase (TIMPs), [[beta].sub.1]-integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were analyzed by Western blots. The levels of pericapillary and interstitial fibrosis were identified by Masson trichrome stains. The levels of apoptosis were measured by identifying the TdT-mediated dUTP nick end labeling (TUNEL)positive cells and caspase-3 levels. The results suggested robust nitrotyrosine and MMP activation at 2 and 6 wk of AVF. The treatment with [H.sub.2]S donor mitigated nitrotyrosine generation and MMP activation (i.e., oxidative and proteolytic stresses). The levels of TIMP-1 and TIMP-3 were increased and TIMP-4 decreased in AVF hearts. The treatment with [H.sub.2]S donor reversed this change in TIMPs levels. The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with [H.sub.2]S donor attenuated the fibrosis, apoptosis, and decrease in integrin. fibrosis; extracellular matrix; ADAM; integrin; matrix metalloproteinase; tissue inhibitor of metalloproteinase; left ventricle hypertrophy; collagen; TUNEL; apoptosis; homocysteine doi: 10.1152/ajpheart.00682.2009

Am J Physiol Regul Integr Comp Physiol 298: R51-R60, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00576.2009.--Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O2-sensing mechanism. Global pulmonary hypoxia experienced by individuals suffering from chronic obstructive pulmonary disease or numerous hypoventilation syndromes, including sleep apnea, often produces maladaptive pulmonary hypertension, but pulmonary hypertension is not observed in diving mammals, where profound hypoxia is routine. Here we examined the response of cow and sea lion pulmonary arteries (PA) to hypoxia and observed the expected HVC in the former and a unique hypoxic vasodilation in resistance vessels in the latter. We then used this disparate response to examine the [O.sub.2]-sensing mechanism. In both animals, exogenous [H.sub.2]S mimicked the vasoactive effects of hypoxia in isolated PA. [H.sub.2]S-synthesizing enzymes, cystathionine [beta]-synthase, cystathionine [gamma]-lyase, and 3-mercaptopyruvate sulfur transferase, were identified in lung tissue from both animals by one-dimensional Western blot analysis and immunohistochemistry. The relationship between [H.sub.2]S production/consumption and [O.sub.2] was examined in real time by use of amperometric [H.sub.2]S and [O.sub.2] sensors. H2S was produced by sea lion and cow lung homogenate in the absence of [O.sub.2], but it was rapidly consumed when [O.sub.2] was present. Furthermore, consumption of exogenous [H.sub.2]S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was [O.sub.2] dependent and exhibited maximal sensitivity at physiologically relevant [Po.sub.2] levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for [O.sub.2]-dependent [H.sub.2]S metabolism in [O.sub.2] sensing. hypoxic vasoconstriction; pinniped; pulmonary hypertension