{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:21:27Z","timestamp":1790068887380,"version":"4.0.1"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2019,8,6]]},"abstract":"\n Background<\/jats:title>\n \n In murine heart failure models and in humans with diabetic\u2010related heart hypertrophy, inhibition of phosphodiesterase 5 (\n PDE<\/jats:styled-content>\n 5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between\n PDE<\/jats:styled-content>\n 5 and \u03b22 adrenergic receptor (\u03b22\n AR<\/jats:styled-content>\n ), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Wild\u2010type and \u03b22\n AR<\/jats:styled-content>\n knockout mice fed a high fat diet (\n HFD<\/jats:styled-content>\n ) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation\u2010contraction (E\u2010C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses.\n PDE<\/jats:styled-content>\n 5 selectively associates with \u03b22\n AR<\/jats:styled-content>\n , but not \u03b21 adrenergic receptor, and inhibition of\n PDE<\/jats:styled-content>\n 5 with sildenafil restores the impaired response to adrenergic stimulation in\n HFD<\/jats:styled-content>\n mice and isolated ventriculomyocytes. Sildenafil enhances \u03b2 adrenergic receptor (\u03b2AR)\u2010stimulated\n cGMP<\/jats:styled-content>\n and\n cAMP<\/jats:styled-content>\n signals in\n HFD<\/jats:styled-content>\n myocytes. Consequently, inhibition of\n PDE<\/jats:styled-content>\n 5 leads to protein kinase G\u2013, and to a lesser extent, calcium\/calmodulin\u2010dependent kinase\n II<\/jats:styled-content>\n \u2013dependent improvements in adrenergically stimulated E\u2010C coupling. Deletion of \u03b22\n AR<\/jats:styled-content>\n abolishes sildenafil's effect. Although the\n PDE<\/jats:styled-content>\n 5\u2010\u03b22\n AR<\/jats:styled-content>\n association is not altered in\n HFD<\/jats:styled-content>\n , phosphodiesterase 3 displays an increased association with the \u03b22\n AR<\/jats:styled-content>\n \u2010\n PDE<\/jats:styled-content>\n 5 complex in\n HFD<\/jats:styled-content>\n myocytes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study elucidates mechanisms by which the \u03b22\n AR<\/jats:styled-content>\n \u2010\n PDE<\/jats:styled-content>\n 5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of\n PDE<\/jats:styled-content>\n 5 enhances \u03b22\n AR<\/jats:styled-content>\n stimulation of\n cGMP<\/jats:styled-content>\n and\n cAMP<\/jats:styled-content>\n signals, as well as protein kinase G\u2013dependent E\u2010C coupling in\n HFD<\/jats:styled-content>\n myocytes.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.119.012273","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T09:06:06Z","timestamp":1563354366000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["Phosphodiesterase 5 Associates With \u03b22 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts"],"prefix":"10.1161","volume":"8","author":[{"given":"Toni M.","family":"West","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingtong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqing","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"},{"name":"Sun\u2010Yet Sen Memorial hospital Sun\u2010Yet Sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"},{"name":"College of Pharmacy Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Barbagallo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"},{"name":"Department of Experimental Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopireddy R.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle S.","family":"Phan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"},{"name":"College of Pharmacy Guangzhou Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Isidori","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang K.","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis School of Medicine Davis CA"},{"name":"VA Northern California Health Care System Mather CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000558"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.211"},{"key":"e_1_3_2_4_2","first-page":"541","volume":"64","author":"Lindman BR","year":"2014","unstructured":"Lindman BR, D\u00e1vila\u2010Rom\u00e1n VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF, Redfield MM. 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