{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:01Z","timestamp":1791907201704,"version":"4.3.4"},"reference-count":60,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,10,4]],"date-time":"2017-10-04T00:00:00Z","timestamp":1507075200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovascular Therapeutics"],"published-print":{"date-parts":[[2017,12]]},"abstract":"Summary<\/jats:title>\n \n Introduction<\/jats:title>\n \n Hyperhomocysteinemia (\n HH<\/jats:styled-content>\n cy) impairs nitric oxide endothelium\u2010dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for\n HH<\/jats:styled-content>\n cy are necessary.\n <\/jats:p>\n <\/jats:sec>\n \n Aim<\/jats:title>\n \n We tested the hypothesis that alamandine, a vasoactive peptide of the renin\u2010angiotensin system (\n RAS<\/jats:styled-content>\n ), could reverse\n HH<\/jats:styled-content>\n cy\u2010induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (\n PKA<\/jats:styled-content>\n ) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations.\n <\/jats:p>\n <\/jats:sec>\n \n Method<\/jats:title>\n \n The abdominal aorta was excised from New Zealand white rabbits (n\u00a0=\u00a015) and incubated with 3 mmol\/L Hcy (to mimic\n HH<\/jats:styled-content>\n cy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine.\n <\/jats:p>\n <\/jats:sec>\n \n Result<\/jats:title>\n \n Vasodilation was significantly impaired in\n HH<\/jats:styled-content>\n cy\u2010incubated aortic rings while alamandine reversed this effect (control, 74.2\u00a0\u00b1\u00a05.0%; Hcy, 30.3\u00a0\u00b1\u00a09.8%; alamandine\u00a0+\u00a0Hcy, 59.7\u00a0\u00b1\u00a04.8%,\n P\u00a0<\/jats:italic>\n <\n \u00a0<\/jats:italic>\n .0001).\n KT<\/jats:styled-content>\n 5720 (\n PKA<\/jats:styled-content>\n inhibitor) significantly inhibited the ability of alamandine to attenuate the impaired vasodilation caused by\n HH<\/jats:styled-content>\n cy (\n KT<\/jats:styled-content>\n 5720\u00a0+\u00a0Hcy\u00a0+\u00a0alamandine, 27.1\u00a0\u00b1\u00a024.1,\n P\u00a0<\/jats:italic>\n <\n \u00a0<\/jats:italic>\n .01). Following immunohistochemistry analysis, the MrgD receptor was highly expressed within the media and endothelial layer of aortic rings in\n HH<\/jats:styled-content>\n cy compared to control (media: 0.23\u00a0\u00b1\u00a00.003 vs control 0.16\u00a0\u00b1\u00a00.01,\n P\u00a0<\/jats:italic>\n <\n \u00a0<\/jats:italic>\n .05 and endothelium: 0.68\u00a0\u00b1\u00a00.07 vs control 0.13\u00a0\u00b1\u00a00.02,\n P\u00a0<\/jats:italic>\n <\n \u00a0<\/jats:italic>\n .01, in\n PA<\/jats:styled-content>\n \/I (A.U) units). Computational studies also propose certain interactions of alamandine within the MrgD transmembrane domain.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study shows that alamandine is effective in reversing\n HH<\/jats:styled-content>\n cy\u2010induced vascular dysfunction, possibly through the\n PKA<\/jats:styled-content>\n signaling pathway via MrgD. Our results indicate a therapeutic potential of alamandine in reversing the detrimental effects of\n HH<\/jats:styled-content>\n cy.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/1755-5922.12306","type":"journal-article","created":{"date-parts":[[2017,9,13]],"date-time":"2017-09-13T07:23:04Z","timestamp":1505287384000},"source":"Crossref","is-referenced-by-count":38,"title":["Alamandine reverses hyperhomocysteinemia\u2010induced vascular dysfunction via\n PKA<\/scp>\n \u2010dependent mechanisms"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2904-5483","authenticated-orcid":false,"given":"Tawar","family":"Qaradakhi","sequence":"first","affiliation":[{"name":"Centre for Chronic Disease, College of Health and Biomedicine Victoria University Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minos Timotheos","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Patras Patras Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Hayes","sequence":"additional","affiliation":[{"name":"Centre for Chronic Disease, College of Health and Biomedicine Victoria University Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Rybalka","sequence":"additional","affiliation":[{"name":"Centre for Chronic Disease, College of Health and Biomedicine Victoria University Melbourne Vic. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Caprnda","sequence":"additional","affiliation":[{"name":"2nd Department of Internal Medicine, Faculty of Medicine Comenius University Bratislava Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kvetoslava","family":"Rimarova","sequence":"additional","affiliation":[{"name":"Department of Public Health and Hygiene, Faculty of Medicine Pavol Jozef Safarik University Kosice Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Sepsi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Cardiology University Hospital Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietrich","family":"B\u00fcsselberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar Qatar Foundation \u2013 Education City Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kruzliak","sequence":"additional","affiliation":[{"name":"Department of Chemical Drugs, Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"ELdrug SA, Patras Science Park Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasso","family":"Apostolopoulos","sequence":"additional","affiliation":[{"name":"Centre for Chronic Disease, College of Health and Biomedicine Victoria University Melbourne Vic. 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