Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms

Tawar Qaradakhi, Minos Timotheos Matsoukas, Alan Hayes, Emma Rybalka, Martin Caprnda, Kvetoslava Rimarova, Milan Sepsi, Dietrich Busselberg, Peter Kruzliak, John Matsoukas, Vasso Apostolopoulos, Anthony Zulli

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Introduction: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. Aim: We 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. Method: The 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. Result: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; 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. Conclusion: This 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.

Original languageEnglish
Article numbere12306
JournalCardiovascular Therapeutics
Volume35
Issue number6
DOIs
Publication statusPublished - 1 Dec 2017

Fingerprint

Hyperhomocysteinemia
Cyclic AMP-Dependent Protein Kinases
Blood Vessels
Vasodilation
Endothelium
alamandine
Abdominal Aorta
Molecular Dynamics Simulation
Protein Kinase Inhibitors
Renin-Angiotensin System
Acetylcholine
Atherosclerosis
Nitric Oxide
Cardiovascular Diseases
Immunohistochemistry
Rabbits
Peptides

Keywords

  • Alamandine
  • Endothelial dysfunction
  • Homocysteine
  • MrgD
  • Protein kinase A

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

Qaradakhi, T., Matsoukas, M. T., Hayes, A., Rybalka, E., Caprnda, M., Rimarova, K., ... Zulli, A. (2017). Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms. Cardiovascular Therapeutics, 35(6), [e12306]. https://doi.org/10.1111/1755-5922.12306

Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms. / Qaradakhi, Tawar; Matsoukas, Minos Timotheos; Hayes, Alan; Rybalka, Emma; Caprnda, Martin; Rimarova, Kvetoslava; Sepsi, Milan; Busselberg, Dietrich; Kruzliak, Peter; Matsoukas, John; Apostolopoulos, Vasso; Zulli, Anthony.

In: Cardiovascular Therapeutics, Vol. 35, No. 6, e12306, 01.12.2017.

Research output: Contribution to journalArticle

Qaradakhi, T, Matsoukas, MT, Hayes, A, Rybalka, E, Caprnda, M, Rimarova, K, Sepsi, M, Busselberg, D, Kruzliak, P, Matsoukas, J, Apostolopoulos, V & Zulli, A 2017, 'Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms', Cardiovascular Therapeutics, vol. 35, no. 6, e12306. https://doi.org/10.1111/1755-5922.12306
Qaradakhi, Tawar ; Matsoukas, Minos Timotheos ; Hayes, Alan ; Rybalka, Emma ; Caprnda, Martin ; Rimarova, Kvetoslava ; Sepsi, Milan ; Busselberg, Dietrich ; Kruzliak, Peter ; Matsoukas, John ; Apostolopoulos, Vasso ; Zulli, Anthony. / Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms. In: Cardiovascular Therapeutics. 2017 ; Vol. 35, No. 6.
@article{74bda88862a748ed8859647108273ebd,
title = "Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms",
abstract = "Introduction: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. Aim: We 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. Method: The 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. Result: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0{\%}; 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. Conclusion: This 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.",
keywords = "Alamandine, Endothelial dysfunction, Homocysteine, MrgD, Protein kinase A",
author = "Tawar Qaradakhi and Matsoukas, {Minos Timotheos} and Alan Hayes and Emma Rybalka and Martin Caprnda and Kvetoslava Rimarova and Milan Sepsi and Dietrich Busselberg and Peter Kruzliak and John Matsoukas and Vasso Apostolopoulos and Anthony Zulli",
year = "2017",
month = "12",
day = "1",
doi = "10.1111/1755-5922.12306",
language = "English",
volume = "35",
journal = "Cardiovascular Therapeutics",
issn = "1755-5914",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms

AU - Qaradakhi, Tawar

AU - Matsoukas, Minos Timotheos

AU - Hayes, Alan

AU - Rybalka, Emma

AU - Caprnda, Martin

AU - Rimarova, Kvetoslava

AU - Sepsi, Milan

AU - Busselberg, Dietrich

AU - Kruzliak, Peter

AU - Matsoukas, John

AU - Apostolopoulos, Vasso

AU - Zulli, Anthony

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Introduction: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. Aim: We 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. Method: The 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. Result: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; 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. Conclusion: This 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.

AB - Introduction: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. Aim: We 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. Method: The 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. Result: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; 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. Conclusion: This 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.

KW - Alamandine

KW - Endothelial dysfunction

KW - Homocysteine

KW - MrgD

KW - Protein kinase A

UR - http://www.scopus.com/inward/record.url?scp=85033467510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033467510&partnerID=8YFLogxK

U2 - 10.1111/1755-5922.12306

DO - 10.1111/1755-5922.12306

M3 - Article

VL - 35

JO - Cardiovascular Therapeutics

JF - Cardiovascular Therapeutics

SN - 1755-5914

IS - 6

M1 - e12306

ER -