{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T09:43:46Z","timestamp":1762076626513,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T00:00:00Z","timestamp":1668470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["19ZR1405500"],"award-info":[{"award-number":["19ZR1405500"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Urotensin II (UII) could increase blood pressure and heart rate via increased central reactive oxygen species (ROS) levels. We reported previously that hydrogen sulfide (H2S) exerts an antihypertensive effect by suppressing ROS production. The aim of the current study is to further examine the effects of endogenous and exogenous H2S on UII-induced cardiovascular effects by using an integrated physiology approach. We also use cell culture and molecular biological techniques to explore the inhibitory role of H2S on UII-induced cardiovascular effects. In this study, we found that cystathionine-\u03b2-synthase (CBS), the main H2S synthesizing enzyme in CNS, was expressed in neuronal cells of the rostral ventrolateral medulla (RVLM) area. Cellular distribution of CBS and urotensin II receptor (UT) in SH-SY5Y cells that are confirmed as glutamatergic were identified by immunofluorescent and Western blots assay. In Sprague\u2013Dawley rats, administration of UII into the RVLM resulted in an increase in mean arterial pressure (MAP), heart rate (HR), ROS production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and phosphorylation of p47phox, extracellular signal-regulated protein kinase (ERK)1\/2 and p38MAPK, but not stress-activated protein kinase\/Jun N-terminal kinase (SAPK\/JNK). These effects of UII were attenuated by application into the RVLM of endogenous (L-cysteine, SAM) or exogenous (NaHS) H2S. These results were confirmed in SH-SY5Y cells. UII-induced cardiovascular effects were also significantly abolished by pretreatment with microinjection of Tempol, Apocynin, SB203580, or PD98059 into the RVLM. Preincubated SH-SY5Y cells with Apocynin before administration of UII followed by Western blots assay showed that ROS is in the upstream of p38MAPK\/ERK1\/2. Gao activation assay in SH-SY5Y cells suggested that H2S may exert an inhibitory role on UII-induced cardiovascular effects by inhibiting the activity of G\u03b1o. These results suggest that both endogenous and exogenous H2S attenuate UII-induced cardiovascular effects via G\u03b1o-ROS-p38MAPK\/ERK1\/2 pathway.<\/jats:p>","DOI":"10.3390\/antiox11112253","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:31:27Z","timestamp":1668565887000},"page":"2253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Inhibitory Role of Hydrogen Sulfide in UII-Induced Cardiovascular Effects and the Underlying Signaling Pathways"],"prefix":"10.3390","volume":"11","author":[{"given":"Na-Na","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Department of Urology, Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Ni","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8889-1594","authenticated-orcid":false,"given":"Yi-Fan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Mei","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3506-5544","authenticated-orcid":false,"given":"Xing-Zhong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/1742-2094-9-212","article-title":"Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation","volume":"9","author":"Wu","year":"2012","journal-title":"J. Neuroinflam."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"927686","DOI":"10.1155\/2015\/927686","article-title":"Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats","volume":"2015","author":"Yu","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/hr.2014.125","article-title":"Hydrogen sulfide treatment reduces blood pressure and oxidative stress in angiotensin II-induced hypertensive mice","volume":"38","author":"Hart","year":"2015","journal-title":"Hypertens. Res. Off. J. Jpn. Soc. Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/10641963.2020.1847128","article-title":"Urotensin-II, oxidative stress, and inflammation increase in hypertensive and resistant hypertensive patients","volume":"43","author":"Guler","year":"2021","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1161\/CIRCRESAHA.109.199018","article-title":"Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension","volume":"105","author":"Chan","year":"2009","journal-title":"Circ. Res."},{"key":"ref_6","first-page":"142","article-title":"[Central reactive oxygen species mediate cardiovascular effects of urotensin II in spontaneously hypertensive rats]","volume":"64","author":"Lu","year":"2012","journal-title":"Sheng Li Xue Bao Acta Physiol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1161\/01.RES.0000185804.79157.C0","article-title":"NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla","volume":"97","author":"Chan","year":"2005","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Scammahorn, J.J., Nguyen, I.T.N., and Bos, E.M. (2021). Fighting Oxidative Stress with Sulfur: Hydrogen Sulfide in the Renal and Cardiovascular Systems. Antioxidants, 10.","DOI":"10.3390\/antiox10030373"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"LaPenna, K.B., Polhemus, D.J., Doiron, J.E., Hidalgo, H.A., Li, Z., and Lefer, D.J. (2021). Hydrogen Sulfide as a Potential Therapy for Heart Failure-Past, Present, and Future. Antioxidants, 10.","DOI":"10.3390\/antiox10030485"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cellsig.2014.01.024","article-title":"NF-\u03baB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A(2A) receptors","volume":"26","author":"Bruzzese","year":"2014","journal-title":"Cell. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"690919","DOI":"10.3389\/fnins.2021.690919","article-title":"Central Administration of Hydrogen Sulfide Donor NaHS Reduces Iba1-Positive Cells in the PVN and Attenuates Rodent Angiotensin II Hypertension","volume":"15","author":"Oliveira","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/MNH.0b013e32832923c3","article-title":"Molecular mechanisms of hypertension: Role of Nox family NADPH oxidases","volume":"18","author":"Sedeek","year":"2009","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.intimp.2016.09.002","article-title":"A urotensin II receptor antagonist, KR36676, decreases vascular remodeling and inflammation in experimental pulmonary hypertension","volume":"40","author":"Lee","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1113\/EP086040","article-title":"Physiological redox signalling and regulation of ion channels: Implications for pulmonary hypertension","volume":"102","author":"Ward","year":"2017","journal-title":"Exp. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s11906-006-0026-7","article-title":"Urotensin-II and cardiovascular diseases","volume":"8","author":"Bousette","year":"2006","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/sj.bjp.0706800","article-title":"The role of urotensin II in cardiovascular and renal physiology and diseases","volume":"148","author":"Zhu","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fnins.2017.00051","article-title":"Central and Peripheral Effects of Urotensin II and Urotensin II-Related Peptides on Cardiac Baroreflex Sensitivity in Trout","volume":"11","author":"Lancien","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1016\/S0196-9781(02)00104-3","article-title":"Cardiovascular effects of urotensin II in different brain areas","volume":"23","author":"Lu","year":"2002","journal-title":"Peptides"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3284769","DOI":"10.1155\/2020\/3284769","article-title":"Association between Plasma Urotensin II and Risk of Hypertension: Findings from a Prospective Study","volume":"2020","author":"Xie","year":"2020","journal-title":"Int. J. Hypertens."},{"key":"ref_20","first-page":"295","article-title":"The role of perivascular adipose tissue and endogenous hydrogen sulfide in vasoactive responses of isolated mesenteric arteries in normotensive and spontaneously hypertensive rats","volume":"70","author":"Cacanyiova","year":"2019","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"H2093","DOI":"10.1152\/ajpheart.00088.2007","article-title":"Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats","volume":"293","author":"Shi","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"H728","DOI":"10.1152\/ajpheart.00404.2021","article-title":"Hydrogen sulfide-dependent microvascular vasodilation is improved following chronic sulfhydryl-donating antihypertensive pharmacotherapy in adults with hypertension","volume":"321","author":"Dillon","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1111\/bph.12825","article-title":"Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats","volume":"172","author":"Snijder","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.cjca.2012.01.017","article-title":"Molecular mechanisms of hypertension--reactive oxygen species and antioxidants: A basic science update for the clinician","volume":"28","author":"Montezano","year":"2012","journal-title":"Can. J. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1089\/ars.2013.5230","article-title":"Brain stem NOS and ROS in neural mechanisms of hypertension","volume":"20","author":"Chan","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1016\/j.freeradbiomed.2006.01.032","article-title":"Reduction in molecular synthesis or enzyme activity of superoxide dismutases and catalase contributes to oxidative stress and neurogenic hypertension in spontaneously hypertensive rats","volume":"40","author":"Chan","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hsu, C.N., and Tain, Y.L. (2021). Preventing Developmental Origins of Cardiovascular Disease: Hydrogen Sulfide as a Potential Target?. Antioxidants, 10.","DOI":"10.3390\/antiox10020247"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Piragine, E., Citi, V., Lawson, K., Calderone, V., and Martelli, A. (2022). Potential Effects of Natural H(2)S-Donors in Hypertension Management. Biomolecules, 12.","DOI":"10.3390\/biom12040581"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1152\/japplphysiol.00610.2012","article-title":"Brain stem oxidative stress and its associated signaling in the regulation of sympathetic vasomotor tone","volume":"113","author":"Chan","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1089\/ars.2012.4585","article-title":"Angiotensin-generated reactive oxygen species in brain and pathogenesis of cardiovascular diseases","volume":"19","author":"Chan","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1291\/hypres.31.2075","article-title":"High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats","volume":"31","author":"Koga","year":"2008","journal-title":"Hypertens. Res. Off. J. Jpn. Soc. Hypertens."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0092-8674(03)00314-3","article-title":"Molecular basis of phosphorylation-induced activation of the NADPH oxidase","volume":"113","author":"Groemping","year":"2003","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1161\/HYPERTENSIONAHA.109.149146","article-title":"Oral intake of rosiglitazone promotes a central antihypertensive effect via upregulation of peroxisome proliferator-activated receptor-gamma and alleviation of oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats","volume":"55","author":"Chan","year":"2010","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"R311","DOI":"10.1152\/ajpregu.00246.2010","article-title":"Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: Role of superoxide anion","volume":"300","author":"Patel","year":"2011","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/ajh.2009.17","article-title":"Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension","volume":"22","author":"Nishi","year":"2009","journal-title":"Am. J. Hypertens."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1097\/HJH.0b013e328217b286","article-title":"Upregulation of AT1 receptor gene on activation of protein kinase Cbeta\/nicotinamide adenine dinucleotide diphosphate oxidase\/ERK1\/2\/c-fos signaling cascade mediates long-term pressor effect of angiotensin II in rostral ventrolateral medulla","volume":"25","author":"Chan","year":"2007","journal-title":"J. Hypertens."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1515\/revneuro-2015-0041","article-title":"Angiotensin II-triggered kinase signaling cascade in the central nervous system","volume":"27","author":"Bali","year":"2016","journal-title":"Rev. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12482","DOI":"10.3390\/ijms160612482","article-title":"Urotensin II Protects Cardiomyocytes from Apoptosis Induced by Oxidative Stress through the CSE\/H2S Pathway","volume":"16","author":"Gong","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_39","first-page":"4998","article-title":"Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK\/ERK signaling pathway","volume":"12","author":"Liu","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1474-9726.2009.00543.x","article-title":"Neuroprotective effects of hydrogen sulfide on Parkinson\u2019s disease rat models","volume":"9","author":"Hu","year":"2010","journal-title":"Aging Cell"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/11\/2253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:18:31Z","timestamp":1760145511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/11\/2253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,15]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["antiox11112253"],"URL":"https:\/\/doi.org\/10.3390\/antiox11112253","relation":{},"ISSN":["2076-3921"],"issn-type":[{"type":"electronic","value":"2076-3921"}],"subject":[],"published":{"date-parts":[[2022,11,15]]}}}