A bivalent antihypertensive vaccine targeting L‐type calcium channels and angiotensin AT₁ receptors

Abstract

Background and Purpose: Hypertension has been the leading preventable cause of premature death worldwide. The aim of this study was to design a more efficient vaccine against novel targets for the treatment of hypertension.Experimental Approach: The epitope CE12, derived from the human L-type calcium channel (Ca V 1.2), was designed and conjugated with Qβ bacteriophage viruslike particles to test the efficacy in hypertensive animals. Further, the hepatitis B core antigen (HBcAg)-CE12-CQ10 vaccine, a bivalent vaccine based on HBcAg virus-like particles and targeting both human angiotensin AT 1 receptors and Ca V 1.2 channels, was developed and evaluated in hypertensive rodents.Key Results: The Qβ-CE12 vaccine effectively decreased the BP in hypertensive rodents. A monoclonal antibody against CE12 specifically bound to L-type calcium channels and inhibited channel activity. Injection with monoclonal antibody against CE12 effectively reduced the BP in angiotensin II-induced hypertensive mice. The HBcAg-CE12-CQ10 vaccine showed antihypertensive effects in hypertensive mice and relatively superior antihypertensive effects in spontaneously hypertensive rats and ameliorated L-NAME-induced renal injury. In addition, no obvious immunemediated damage or electrophysiological adverse effects were detected.Conclusion and Implications: Immunotherapy against both AT 1 receptors and Ca V 1.2 channels decreased the BP in hypertensive rodents effectively and provided protection against hypertensive target organ damage without obvious feedback activation of renin-angiotensin system or induction of dominant antibodies against the carrier protein. Thus, the HBcAg-CE12-CQ10 vaccine may provide a novel and promising therapeutic approach for hypertension.

Pathological AT1R-B2R Protein Aggregation and Preeclampsia

“…An alternative approach could target AT1R (AT1R-B2R), and the L-type calcium channel simultaneously [135]. The experimental strategy uses a bivalent vaccine against the AT1 receptor and the L-type calcium channel, and thereby simultaneously inhibits the AT1 receptor and the Cav 1.2 channels as the major L-type calcium channel in humans [135].…”

“…An alternative approach could target AT1R (AT1R-B2R), and the L-type calcium channel simultaneously [135]. The experimental strategy uses a bivalent vaccine against the AT1 receptor and the L-type calcium channel, and thereby simultaneously inhibits the AT1 receptor and the Cav 1.2 channels as the major L-type calcium channel in humans [135]. The bivalent vaccine effectively lowered blood pressure and prevented end-organ damage in experimental models of hypertension in mice and rats, without major side effects [135].…”

Therapeutic vaccine for chronic diseases after the COVID-19 Era

“…Wu et al reported the development of vaccines with VLPs against the L-type calcium channel for the treatment of hypertension in SHRs [ 36 ]. A peptide (named CE12) was derived from the epitope of the third extracellular region of domain IV of the human L-type calcium channel [ 37 , 38 ], and after four injections, systolic BP was significantly decreased in vaccinated SHRs compared with unvaccinated rats.…”

Future Directions of Therapeutic Vaccines for Chronic Diseases

“…Wu et al reported the development of vaccines against the L-type calcium channel for treatment of hypertension in SHRs. 42 The peptide (named CE12) was derived from the epitope of the third extracellular region of domain IV of the human L-type calcium channel, which plays an important role in allosteric modulation after binding to 1,4-dihydropyridines. 43,44 They used a VLP as a carrier protein.…”