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@article{1399059,
author = {Qaradakhi, T.. and Matsoukas, M.T. and Hayes, A. and Rybalka, E. and Caprnda, M. and Rimarova, K. and Sepši, Milan and Busselberg, D. and Kružliak, Peter and Matsoukas, J. and Apostolopoulos, V. and Zulli, A.},
article_location = {HOBOKEN},
article_number = {6},
doi = {http://dx.doi.org/10.1111/1755-5922.12306},
keywords = {Alamandine; Endothelial dysfunction; Homocysteine; MrgD; Protein kinase A},
language = {eng},
issn = {1755-5914},
journal = {CARDIOVASCULAR THERAPEUTICS},
title = {Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms},
url = {http://dx.doi.org/10.1111/1755-5922.12306},
volume = {35},
year = {2017}
}
TY - JOUR
ID - 1399059
AU - Qaradakhi, T.. - Matsoukas, M.T. - Hayes, A. - Rybalka, E. - Caprnda, M. - Rimarova, K. - Sepši, Milan - Busselberg, D. - Kružliak, Peter - Matsoukas, J. - Apostolopoulos, V. - Zulli, A.
PY - 2017
TI - Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms
JF - CARDIOVASCULAR THERAPEUTICS
VL - 35
IS - 6
SP - 1-11
EP - 1-11
PB - WILEY
SN - 17555914
KW - Alamandine
KW - Endothelial dysfunction
KW - Homocysteine
KW - MrgD
KW - Protein kinase A
UR - http://dx.doi.org/10.1111/1755-5922.12306
L2 - http://dx.doi.org/10.1111/1755-5922.12306
N2 - IntroductionHyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. AimWe tested the hypothesis that alamandine, a vasoactive peptide of the renin-angiotensin system (RAS), could reverse HHcy-induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (PKA) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations. MethodThe abdominal aorta was excised from New Zealand white rabbits (n=15) and incubated with 3 mmol/L Hcy (to mimic HHcy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine. ResultVasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.25.0%; Hcy, 30.3 +/- 9.8%; alamandine+Hcy, 59.7 +/- 4.8%, P<.0001). KT5720 (PKA inhibitor) significantly inhibited the ability of alamandine to attenuate the impaired vasodilation caused by HHcy (KT5720+Hcy+alamandine, 27.1 +/- 24.1, P<.01). Following immunohistochemistry analysis, the MrgD receptor was highly expressed within the media and endothelial layer of aortic rings in HHcy compared to control (media: 0.23 +/- 0.003 vs control 0.16 +/- 0.01, P<.05 and endothelium: 0.68 +/- 0.07 vs control 0.13 +/- 0.02, P<.01, in PA/I (A.U) units). Computational studies also propose certain interactions of alamandine within the MrgD transmembrane domain. ConclusionThis study shows that alamandine is effective in reversing HHcy-induced vascular dysfunction, possibly through the PKA signaling pathway via MrgD. Our results indicate a therapeutic potential of alamandine in reversing the detrimental effects of HHcy.
ER -
QARADAKHI, T.., M.T. MATSOUKAS, A. HAYES, E. RYBALKA, M. CAPRNDA, K. RIMAROVA, Milan SEPŠI, D. BUSSELBERG, Peter KRUŽLIAK, J. MATSOUKAS, V. APOSTOLOPOULOS and A. ZULLI. Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms. \textit{CARDIOVASCULAR THERAPEUTICS}. HOBOKEN: WILEY, 2017, vol.~35, No~6, p.~1-11. ISSN~1755-5914. Available from: https://dx.doi.org/10.1111/1755-5922.12306.
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