Alamandine reverses hyperhomocysteinemia-induced vasculardysfunction via PKA-dependent mechanisms
2017
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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI