PMID- 28901725
OWN - NLM
STAT- MEDLINE
DCOM- 20180629
LR  - 20180629
IS  - 1755-5922 (Electronic)
IS  - 1755-5914 (Linking)
VI  - 35
IP  - 6
DP  - 2017 Dec
TI  - Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via 
      PKA-dependent mechanisms.
LID - 10.1111/1755-5922.12306 [doi]
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.
CI  - (c) 2017 John Wiley & Sons Ltd.
FAU - Qaradakhi, Tawar
AU  - Qaradakhi T
AUID- ORCID: 0000-0003-2904-5483
AD  - Centre for Chronic Disease, College of Health and Biomedicine, Victoria 
      University, Melbourne, Vic., Australia.
FAU - Matsoukas, Minos Timotheos
AU  - Matsoukas MT
AD  - Department of Pharmacy, University of Patras, Patras, Greece.
FAU - Hayes, Alan
AU  - Hayes A
AD  - Centre for Chronic Disease, College of Health and Biomedicine, Victoria 
      University, Melbourne, Vic., Australia.
FAU - Rybalka, Emma
AU  - Rybalka E
AD  - Centre for Chronic Disease, College of Health and Biomedicine, Victoria 
      University, Melbourne, Vic., Australia.
FAU - Caprnda, Martin
AU  - Caprnda M
AD  - 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, 
      Bratislava, Slovakia.
FAU - Rimarova, Kvetoslava
AU  - Rimarova K
AD  - Department of Public Health and Hygiene, Faculty of Medicine, Pavol Jozef Safarik 
      University, Kosice, Slovakia.
FAU - Sepsi, Milan
AU  - Sepsi M
AD  - Department of Internal Medicine and Cardiology, University Hospital, Brno, Czech 
      Republic.
FAU - Busselberg, Dietrich
AU  - Busselberg D
AD  - Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, 
      Qatar Foundation - Education City, Doha, Qatar.
FAU - Kruzliak, Peter
AU  - Kruzliak P
AD  - Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and 
      Pharmaceutical Sciences, Brno, Czech Republic.
FAU - Matsoukas, John
AU  - Matsoukas J
AD  - ELdrug SA, Patras Science Park, Patras, Greece.
FAU - Apostolopoulos, Vasso
AU  - Apostolopoulos V
AD  - Centre for Chronic Disease, College of Health and Biomedicine, Victoria 
      University, Melbourne, Vic., Australia.
FAU - Zulli, Anthony
AU  - Zulli A
AD  - Centre for Chronic Disease, College of Health and Biomedicine, Victoria 
      University, Melbourne, Vic., Australia.
LA  - eng
PT  - Journal Article
DEP - 20171004
PL  - England
TA  - Cardiovasc Ther
JT  - Cardiovascular therapeutics
JID - 101319630
RN  - 0 (Carbazoles)
RN  - 0 (Oligopeptides)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrroles)
RN  - 0 (alamandine)
RN  - 58HV29I28S (KT 5720)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - Animals
MH  - Aorta, Abdominal/drug effects
MH  - Carbazoles/pharmacology
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Hyperhomocysteinemia/*complications/*drug therapy
MH  - In Vitro Techniques
MH  - Male
MH  - Molecular Docking Simulation
MH  - Oligopeptides/*therapeutic use
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Pyrroles/pharmacology
MH  - Rabbits
MH  - Signal Transduction/drug effects
MH  - Vascular Diseases/*drug therapy/*etiology
OTO - NOTNLM
OT  - Alamandine
OT  - Endothelial dysfunction
OT  - Homocysteine
OT  - MrgD
OT  - Protein kinase A
EDAT- 2017/09/14 06:00
MHDA- 2018/06/30 06:00
CRDT- 2017/09/14 06:00
PHST- 2017/06/04 00:00 [received]
PHST- 2017/08/30 00:00 [revised]
PHST- 2017/09/08 00:00 [accepted]
PHST- 2017/09/14 06:00 [pubmed]
PHST- 2018/06/30 06:00 [medline]
PHST- 2017/09/14 06:00 [entrez]
AID - 10.1111/1755-5922.12306 [doi]
PST - ppublish
SO  - Cardiovasc Ther. 2017 Dec;35(6). doi: 10.1111/1755-5922.12306. Epub 2017 Oct 4.