{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:13:13Z","timestamp":1791144793976,"version":"4.1.0"},"reference-count":131,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 HL174841, P01 HL075443, P01 HL134608, P01 HL091799, R01 HL 061690"],"award-info":[{"award-number":["P01 HL174841, P01 HL075443, P01 HL134608, P01 HL091799, R01 HL 061690"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015891","name":"AHA","doi-asserted-by":"publisher","award":["18MERIT33900036"],"award-info":[{"award-number":["18MERIT33900036"]}],"id":[{"id":"10.13039\/501100015891","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac diseases including heart failure (HF), are the leading cause of morbidity and mortality globally. Among the prominent characteristics of HF is the loss of \u03b2-adrenoceptor (AR)-mediated inotropic reserve. This is primarily due to the derangements in myocardial regulatory signaling proteins, G protein-coupled receptor (GPCR) kinases (GRKs) and \u03b2-arrestins (\u03b2-Arr) that modulate \u03b2-AR signal termination via receptor desensitization and downregulation. GRK2 and \u03b2-Arr2 activities are elevated in the heart after injury\/stress and participate in HF through receptor inactivation. These GPCR regulators are modulated profoundly by nitric oxide (NO) produced by NO synthase (NOS) enzymes through S-nitrosylation due to receptor-coupled NO generation. S-nitrosylation, which is NO-mediated modification of protein cysteine residues to generate an S-nitrosothiol (SNO), mediates many effects of NO independently from its canonical guanylyl cyclase\/cGMP\/protein kinase G signaling. Herein, we review the knowledge on the NO system in the heart and S-nitrosylation-dependent modifications of myocardial GPCR signaling components GRKs and \u03b2-Arrs.<\/jats:p>","DOI":"10.3390\/ijms22020521","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T01:51:58Z","timestamp":1609984318000},"page":"521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Nitric Oxide and S-Nitrosylation in Cardiac Regulation: G Protein-Coupled Receptor Kinase-2 and \u03b2-Arrestins as Targets"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-9438","authenticated-orcid":false,"given":"Gizem","family":"Kayki-Mutlu","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA"},{"name":"Faculty of Pharmacy, Department of Pharmacology, Ankara University, Tandogan, 06560 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8522-530X","authenticated-orcid":false,"given":"Walter J.","family":"Koch","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/s41569-019-0220-3","article-title":"G protein-coupled receptor kinases as therapeutic targets in the heart","volume":"16","author":"Pfleger","year":"2019","journal-title":"Nat. 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