Novel Retro-Inverso Peptide Inhibitor Reverses Angiotensin Receptor Autoantibody–Induced Hypertension in the Rabbit

Li, Hongliang; Kem, David C.; Zhang, Ling; Huang, Bing; Liles, Campbell; Benbrook, Alexandria; Gali, Hariprasad; Veitla, Vineet; Scherlag, Benjamin J.; Cunningham, Madeleine W.; Yu, Xichun

doi:10.1161/hypertensionaha.114.05037

Cited by 27 publications

(28 citation statements)

References 31 publications

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“…We also demonstrated significant AT1R‐AAb activity, along with α1AR‐AAb activity, in another 8 of the original 17 subjects. IgG from 4 of the patients with POTS who were positive for AT1R‐AAb showed a significant shift of their dosage response curve to the right compared with that from Ang II alone and confirmed our original report of an inhibitory allosteric impact of AT1R‐AAb on the natural receptor ligand Ang II 10. The AT1R‐AAbs, therefore, appear to act as a partial agonist in vitro.…”

Section: Discussionsupporting

confidence: 83%

“…AT1R‐AAb produced in a rabbit model attenuated the Ang II–induced vasoconstriction10 and may lead to an impaired vascular response, similar to that induced by α1AR‐AAb 6, 7. In the present study, the minimal BP during passive orthostatic challenge was significantly lower in AT1R‐AAb–positive patients with POTS compared with AT1R‐AAb–negative patients with POTS.…”

Section: Discussionsupporting

confidence: 50%

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Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

Murphy

et al. 2018

JAHA

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BackgroundBoth the adrenergic and renin‐angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome (POTS). Activating autoantibodies to the α1‐adrenergic and β1/2‐adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor (AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS.Methods and ResultsSerum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and α1‐adrenergic receptor.ConclusionsMost patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 50%

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

Murphy

et al. 2018

JAHA

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“…16, 18 Briefly, arteriolar segments were microdissected from the cremaster muscle of anesthetized rats and cannulated with glass micropipettes. After equilibration and development of steady-state myogenic tone, the arterioles were perifused with rabbit sera.…”

Section: Methodsmentioning

confidence: 99%

“…16 These animals were immunized with a peptide containing the known functional AT1R-AAb epitope in the ECL2 of AT1R. After immunization, all animals developed elevated blood pressure.…”

Section: Introductionmentioning

confidence: 99%

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

Liles

Veitla

et al. 2015

Hypertension

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Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II (Ang II) and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with Ang II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on Ang II-induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental Ang II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared to normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for study of their roles in blood pressure regulation and possible therapeutic intervention.

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“…RI peptides, in which D-amino acids are substituted for L-amino acids in a reversed sequence, mimic the structure and antigenicity of the natural L-peptides but are resistant to protease degradation [17]. We have successfully used this approach recently to inhibit angiotensin receptor autoantibody-induced hypertension in the rabbit [18]. Here, we demonstrate that such an agent can also effectively block the arrhythmogenic effect of β1AR autoantibodies in immunized rabbits.…”

Section: Introductionmentioning

confidence: 99%

A peptidomimetic inhibitor suppresses the inducibility of β1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit

Zhang

Huang

et al. 2015

J Interv Card Electrophysiol

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Purpose Previous studies demonstrated that burst pacing and subthreshold infusion of acetylcholine in β1-adrenergic receptor (β1AR)-immunized rabbits induced sustained sinus tachycardia. The aim of this study was to examine the anti-arrhythmogenic effect of a newly designed retro-inverso (RI) peptidomimetic inhibitor that specifically targets the β1AR antibodies in the rabbit. Methods Six New Zealand white rabbits were immunized with a β1AR second extracellular loop peptide to produce sympathomimetic β1AR antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with the RI peptide inhibitor. Each rabbit served as its own control. Results No sustained arrhythmias were induced at preimmune baseline. At 6 weeks after immunization, there was a marked increase in induced sustained tachyarrhythmias, predominantly sinus tachycardia, which was largely suppressed by the RI peptide. The atrial effective refractory period was shortened significantly in immunized rabbits compared to their preimmune state. The RI peptide reversed and prolonged this shortening. β1AR antibody levels were negatively correlated with the atrial effective refractory period. Postimmune sera-induced β1AR activation in transfected cells in vitro was also blocked by the RI peptide. Conclusions β1AR-activating autoantibodies are associated with reduction of the atrial effective refractory period and facilitate arrhythmia induction in this model. The RI peptide reversal may have important therapeutic implications in subjects who harbor these autoantibodies.

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Novel Retro-Inverso Peptide Inhibitor Reverses Angiotensin Receptor Autoantibody–Induced Hypertension in the Rabbit

Cited by 27 publications

References 31 publications

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

A peptidomimetic inhibitor suppresses the inducibility of β1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit

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