{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:32:19Z","timestamp":1790645539639,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,8,12]],"date-time":"2015-08-12T00:00:00Z","timestamp":1439337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Hong Kong Research Grant Committee","award":["TBRS T13\u2013706\/11"],"award-info":[{"award-number":["TBRS T13\u2013706\/11"]}]},{"name":"Hong Kong Research Grant Committee","award":["AoE\/M-05\/12"],"award-info":[{"award-number":["AoE\/M-05\/12"]}]},{"name":"Hong Kong Research Grant Committee","award":["CUHK478413"],"award-info":[{"award-number":["CUHK478413"]}]},{"name":"China National Science Foundation","award":["31470912"],"award-info":[{"award-number":["31470912"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cardiac hypertrophy is an abnormal enlargement of heart muscle. It frequently results in congestive heart failure, which is a leading cause of human death. Previous studies demonstrated that the nitric oxide (NO), cyclic GMP (cGMP), and protein kinase G (PKG) signaling pathway can inhibit cardiac hypertrophy and thus improve cardiac function. However, the underlying mechanisms are not fully understood. Here, based on the human embryonic stem cell-derived cardiomyocyte (hESC-CM) model system, we showed that Orai1, the pore-forming subunit of store-operated Ca2+ entry (SOCE), is the downstream effector of PKG. Treatment of hESC-CMs with an \u03b1-adrenoceptor agonist phenylephrine (PE) caused a marked hypertrophy, which was accompanied by an upregulation of Orai1. Moreover, suppression of Orai1 expression\/activity using Orai1-siRNAs or a dominant-negative construct Orai1G98A inhibited the hypertrophy, suggesting that Orai1-mediated SOCE is indispensable for the PE-induced hypertrophy of hESC-CMs. In addition, the hypertrophy was inhibited by NO and cGMP via activating PKG. Importantly, substitution of Ala for Ser34 in Orai1 abolished the antihypertrophic effects of NO, cGMP, and PKG. Furthermore, PKG could directly phosphorylate Orai1 at Ser34 and thus prevent Orai1-mediated SOCE. Together, we conclude that NO, cGMP, and PKG inhibit the hypertrophy of hESC-CMs via PKG-mediated phosphorylation on Orai1-Ser-34. These results provide novel mechanistic insights into the action of cGMP-PKG-related antihypertrophic agents, such as NO donors and sildenafil. Stem Cells \u00a02015;33:2973\u20132984<\/jats:p>","DOI":"10.1002\/stem.2118","type":"journal-article","created":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T04:25:20Z","timestamp":1439439920000},"page":"2973-2984","source":"Crossref","is-referenced-by-count":44,"title":["Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes"],"prefix":"10.1093","volume":"33","author":[{"given":"Y.","family":"Wang","sequence":"first","affiliation":[{"name":"Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, Faculty of Medicine the Chinese University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"Shenzhen Research Institute The Chinese University of Hong Kong, Shenzhen, People's Republic of China"},{"name":"Department of Hematology, The 3rd Xiangya Hospital Central South University, Changsha, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. C.","family":"Li","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, Faculty of Medicine the Chinese University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"Shenzhen Research Institute The Chinese University of Hong Kong, Shenzhen, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, Faculty of Medicine the Chinese University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"Shenzhen Research Institute The Chinese University of Hong Kong, Shenzhen, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Poon","sequence":"additional","affiliation":[{"name":"Stem Cell and Regenerative Medicine Consortium The University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"The Department of Physiology The University of Hong Kong, Hong Kong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. W.","family":"Kong","sequence":"additional","affiliation":[{"name":"Stem Cell and Regenerative Medicine Consortium The University of Hong Kong, Hong Kong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. R.","family":"Boheler","sequence":"additional","affiliation":[{"name":"Stem Cell and Regenerative Medicine Consortium The University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"The Department of Physiology The University of Hong Kong, Hong Kong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Huang","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, Faculty of Medicine the Chinese University of Hong Kong, Hong Kong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. A.","family":"Li","sequence":"additional","affiliation":[{"name":"Stem Cell and Regenerative Medicine Consortium The University of Hong Kong, Hong Kong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Yao","sequence":"additional","affiliation":[{"name":"Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, Faculty of Medicine the Chinese University of Hong Kong, Hong Kong, People's Republic of China"},{"name":"Shenzhen Research Institute The Chinese University of Hong Kong, Shenzhen, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,8,12]]},"reference":[{"key":"2022011112144664300_stem2118-bib-0001","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1089\/ars.2007.1474","article-title":"Cardiac hypertrophy: Mechanisms and therapeutic opportunities","volume":"9","author":"Gupta","year":"2007","journal-title":"Antioxid Redox Signal"},{"key":"2022011112144664300_stem2118-bib-0002","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.vascn.2013.11.002","article-title":"Low-density plating is sufficient to induce cardiac hypertrophy and electrical remodeling in highly purified human iPS cell-derived cardiomyocytes","volume":"69","author":"Uesugi","year":"2014","journal-title":"J Pharmacol Toxicol Method"},{"key":"2022011112144664300_stem2118-bib-0003","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.yjmcc.2010.10.029","article-title":"Modulation of human embryonic stem cell-derived cardiomyocyte growth: A testbed for studying human cardiac hypertrophy?","volume":"50","author":"F\u00f6ldes","year":"2011","journal-title":"J Mol Cell Cardiol"},{"key":"2022011112144664300_stem2118-bib-0004","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.stemcr.2014.09.002","article-title":"Aberrant a-Adrenergic hypertrophic response in cardiomyocytes from human induced pluripotent cells","volume":"3","author":"Gabor","year":"2014","journal-title":"Stem Cell Reports"},{"key":"2022011112144664300_stem2118-bib-0005","doi-asserted-by":"crossref","first-page":"14266","DOI":"10.1074\/jbc.M107167200","article-title":"Capacitative calcium entry contributes to nuclear factor of activated T-cells nuclear translocation and hypertrophy in cardiomyocytes","volume":"277","author":"Hunton","year":"2002","journal-title":"J Biol Chem"},{"key":"2022011112144664300_stem2118-bib-0006","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1253\/circj.CJ-12-0664","article-title":"Cyclic GMP-dependent signaling in cardiac myocytes","volume":"76","author":"Takimoto","year":"2012","journal-title":"Circ J"},{"key":"2022011112144664300_stem2118-bib-0007","doi-asserted-by":"crossref","first-page":"a003970","DOI":"10.1101\/cshperspect.a003970","article-title":"Store-operated calcium channels: New perspectives on mechanism and function","volume":"3","author":"Lewis","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2022011112144664300_stem2118-bib-0008","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nrm3414","article-title":"STIM proteins: Dynamic calcium signal transducers","volume":"13","author":"Soboloff","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022011112144664300_stem2118-bib-0009","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.yjmcc.2010.01.020","article-title":"Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes","volume":"48","author":"Voelkers","year":"2010","journal-title":"J Mol Cell Cardiol"},{"key":"2022011112144664300_stem2118-bib-0010","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1161\/CIRCULATIONAHA.111.031229","article-title":"Critical role for stromal interaction molecule 1 in cardiac hypertrophy","volume":"124","author":"Hulot","year":"2011","journal-title":"Circulation"},{"key":"2022011112144664300_stem2118-bib-0011","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.pharmthera.2009.02.009","article-title":"Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics","volume":"122","author":"Tsai","year":"2009","journal-title":"Pharmacol Ther"},{"key":"2022011112144664300_stem2118-bib-0012","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1161\/01.CIR.99.18.2396","article-title":"Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy","volume":"99","author":"Matter","year":"1999","journal-title":"Circulation"},{"key":"2022011112144664300_stem2118-bib-0013","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0022-2828(03)00079-8","article-title":"Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice","volume":"35","author":"Barouch","year":"2003","journal-title":"J Mol Cell Cardiol"},{"key":"2022011112144664300_stem2118-bib-0014","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1093\/eurheartj\/ehr445","article-title":"Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I","volume":"34","author":"Frantz","year":"2013","journal-title":"Eur Heart J"},{"key":"2022011112144664300_stem2118-bib-0015","doi-asserted-by":"crossref","first-page":"11363","DOI":"10.1073\/pnas.162100799","article-title":"Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes","volume":"99","author":"Fiedler","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011112144664300_stem2118-bib-0016","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1161\/CIRCRESAHA.109.208314","article-title":"Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart","volume":"106","author":"Kinoshita","year":"2010","journal-title":"Circ Res"},{"key":"2022011112144664300_stem2118-bib-0017","doi-asserted-by":"crossref","first-page":"13244","DOI":"10.1074\/jbc.M109.074104","article-title":"Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition","volume":"285","author":"Nishida","year":"2010","journal-title":"J Biol Chem"},{"key":"2022011112144664300_stem2118-bib-0018","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1161\/CIRCULATIONAHA.107.732990","article-title":"Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart","volume":"117","author":"Tokudome","year":"2008","journal-title":"Circulation"},{"key":"2022011112144664300_stem2118-bib-0019","doi-asserted-by":"crossref","first-page":"6758","DOI":"10.1074\/jbc.275.10.6758","article-title":"Store-operated calcium entry in vascular endothelial cells is inhibited by cGMP via a protein kinase G-dependent mechanism","volume":"275","author":"Kwan","year":"2000","journal-title":"J Biol Chem"},{"key":"2022011112144664300_stem2118-bib-0020","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1113\/jphysiol.2001.013258","article-title":"Nitric oxide inhibits capacitative Ca2+ entry and enhances endoplasmic reticulum Ca2+ uptake in bovine vascular endothelial cells","volume":"539","author":"Dedkova","year":"2002","journal-title":"J Physiol"},{"key":"2022011112144664300_stem2118-bib-0021","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1089\/scd.2013.0509","article-title":"A simple, cost-effective but highly efficient system for deriving ventricular cardiomyocytes from human pluripotent stem cells","volume":"23","author":"Weng","year":"2014","journal-title":"Stem Cells Dev"},{"key":"2022011112144664300_stem2118-bib-0022","first-page":"e52010","article-title":"High efficiency differentiation of human pluripotent stem cells to cardiomyocytes and characterization by flow cytometry","volume":"91","author":"Bhattacharya","year":"2014","journal-title":"J Vis Exp"},{"key":"2022011112144664300_stem2118-bib-0023","doi-asserted-by":"crossref","first-page":"E1848","DOI":"10.1073\/pnas.1200250109","article-title":"Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling","volume":"109","author":"Lian","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011112144664300_stem2118-bib-0024","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ccr.2008.12.019","article-title":"Orai1 and STIM1 are critical for breast tumor cell migration and metastasis","volume":"15","author":"Yang","year":"2009","journal-title":"Cancer Cell"},{"key":"2022011112144664300_stem2118-bib-0025","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1126\/science.1127883","article-title":"CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry","volume":"312","author":"Vig","year":"2006","journal-title":"Science"},{"key":"2022011112144664300_stem2118-bib-0026","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1161\/01.HYP.0000102863.23854.0B","article-title":"Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes","volume":"42","author":"Karmazyn","year":"2003","journal-title":"Hypertension"},{"key":"2022011112144664300_stem2118-bib-0027","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.yexcr.2007.12.009","article-title":"Krp1 (Sarcosin) promotes lateral fusion of myofibril assembly intermediates in cultured mouse cardiomyocytes","volume":"314","author":"Greenberg","year":"2008","journal-title":"Exp Cell Res"},{"key":"2022011112144664300_stem2118-bib-0028","doi-asserted-by":"crossref","first-page":"6434","DOI":"10.1074\/jbc.M512905200","article-title":"Vangl1 protein acts as a downstream effector of intestinal trefoil factor (ITF)\/TFF3 signaling and regulates wound healing of intestinal epithelium","volume":"281","author":"Kalabis","year":"2006","journal-title":"J Biol Chem"},{"key":"2022011112144664300_stem2118-bib-0029","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1038\/ncomms4561","article-title":"Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice","volume":"5","author":"Tomimatsu","year":"2014","journal-title":"Nat Commun"},{"key":"2022011112144664300_stem2118-bib-0030","doi-asserted-by":"crossref","first-page":"17838","DOI":"10.1073\/pnas.1114821108","article-title":"Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91","volume":"108","author":"Zhang","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011112144664300_stem2118-bib-0031","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1161\/01.RES.0000043282.39776.7C","article-title":"Galpha(12\/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy","volume":"91","author":"Maruyama","year":"2002","journal-title":"Circ Res"},{"key":"2022011112144664300_stem2118-bib-0032","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1161\/HYPERTENSIONAHA.109.146449","article-title":"Accelerated development of pressure overload\u2013induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model","volume":"55","author":"Oort","year":"2010","journal-title":"Hypertension"},{"key":"2022011112144664300_stem2118-bib-0033","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/0304-3940(91)90239-P","article-title":"Comparative effects of some nitric oxide donors on cyclic GMP levels in rat cerebellar slices","volume":"130","author":"Southam","year":"1991","journal-title":"Neurosci Lett"},{"key":"2022011112144664300_stem2118-bib-0034","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1172\/JCI119883","article-title":"Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts","volume":"101","author":"Calderone","year":"1998","journal-title":"J Clin Invest"},{"key":"2022011112144664300_stem2118-bib-0035","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s12012-007-0028-y","article-title":"eNOS deficient mice develop progressive cardiac hypertrophy with altered cytokine and calcium handling protein expression","volume":"7","author":"Flaherty","year":"2007","journal-title":"Cardiovasc Toxicol"},{"key":"2022011112144664300_stem2118-bib-0036","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1023\/A:1011453809750","article-title":"The role of nitric oxide in the failing heart","volume":"6","author":"Paulus","year":"2001","journal-title":"Heart Fail Rev"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2118","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.2118","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.2118","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/33\/10\/2973\/42015896\/stmcls_33_10_2973.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/33\/10\/2973\/42015896\/stmcls_33_10_2973.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T02:56:26Z","timestamp":1642560986000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/33\/10\/2973-2984\/6407369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,12]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2015,8,12]]},"published-print":{"date-parts":[[2015,10,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.2118","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,10,1]]},"published":{"date-parts":[[2015,8,12]]}}}