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2015 ; 65
(4
): 793-9
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Novel retro-inverso peptide inhibitor reverses angiotensin receptor
autoantibody-induced hypertension in the rabbit
#MMPMID25691619
Li H
; Kem DC
; Zhang L
; Huang B
; Liles C
; Benbrook A
; Gali H
; Veitla V
; Scherlag BJ
; Cunningham MW
; Yu X
Hypertension
2015[Apr]; 65
(4
): 793-9
PMID25691619
show ga
Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been
implicated in hypertensive disorders. We investigated whether AT1R antibodies
produced in immunized rabbits will activate AT1R and contribute to hypertension
by a direct contractile effect on the vasculature and whether they can be blocked
by a novel decoy peptide. A multiple antigenic peptide containing the AT1R
epitope AFHYESQ, which is the receptor-binding epitope of AT1R-activating
autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was
analyzed in AT1R-transfected cells, and their contractile effects were assayed
using isolated perfused rat cremaster resistance arterioles. A retro-inverso
D-amino acid epitope-mimetic peptide was tested for AT1R antibody inhibition in
vitro and in vivo. All immunized animals produced high AT1R antibody titers and
developed elevated blood pressure. No changes in measured blood chemistry values
were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R
activation in transfected cells and vasoconstriction in the arteriole assay, both
of which were blocked by losartan and the retro-inverso D-amino acid peptide. A
single intravenous bolus injection of the retro-inverso d-amino acid peptide (1
mg/kg) into immunized rabbits dropped the mean arterial pressure from 122±11 to
82±6 mm?Hg. Rabbit anti-AT1R sera partially suppressed angiotensin II-induced
contraction of isolated rat cremaster arterioles, and the pressor response to
angiotensin II infusion was attenuated in immunized animals. In conclusion,
AT1R-activating autoantibodies and the retro-inverso d-amino acid peptide,
respectively, have important etiologic and therapeutic implications in
hypertensive subjects who harbor these autoantibodies.
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