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Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline\u2010rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16483","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T05:46:45Z","timestamp":1719985605000},"page":"4174-4194","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of proline\u2010rich tyrosine kinase 2 restores cardioprotection by remote ischaemic preconditioning in type 2 diabetes"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3373-652X","authenticated-orcid":false,"given":"Ralf","family":"Erkens","sequence":"first","affiliation":[{"name":"Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty Heinrich Heine University  Duesseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos 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