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

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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

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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., 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, 35(6), [e12306]. https://doi.org/10.1111/1755-5922.12306