Hailang Wu1,2,3, Yiyi Wang1,2,3, Gongxin Wang4, Zhihua Qiu1,2,3, Xiajun Hu1,2,3, Hongrong Zhang1,2,3, Xiaole Yan1,2,3, Fan Ke1,2,3, Anruo Zou4, Min Wang1,2,3, Yuhua Liao1,2,3, Xiao Chen1,2,3. 1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3. Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 4. Electrophysiological Laboratory, Qingdao Haiwei Biopharma Co. Ltd, Qingdao, China.
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 (CaV 1.2), was designed and conjugated with Qβ bacteriophage virus-like 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 AT1 receptors and CaV 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 immune-mediated damage or electrophysiological adverse effects were detected. CONCLUSION AND IMPLICATIONS: Immunotherapy against both AT1 receptors and CaV 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.
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 humanL-type calcium channel (CaV 1.2), was designed and conjugated with Qβ bacteriophage virus-like 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 AT1 receptors and CaV 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 hypertensivemice. The HBcAg-CE12-CQ10 vaccine showed antihypertensive effects in hypertensivemice and relatively superior antihypertensive effects in spontaneously hypertensiverats and ameliorated L-NAME-induced renal injury. In addition, no obvious immune-mediated damage or electrophysiological adverse effects were detected. CONCLUSION AND IMPLICATIONS: Immunotherapy against both AT1 receptors and CaV 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.
Authors: Giuseppe Mancia; Robert Fagard; Krzysztof Narkiewicz; Josep Redon; Alberto Zanchetti; Michael Böhm; Thierry Christiaens; Renata Cifkova; Guy De Backer; Anna Dominiczak; Maurizio Galderisi; Diederick E Grobbee; Tiny Jaarsma; Paulus Kirchhof; Sverre E Kjeldsen; Stéphane Laurent; Athanasios J Manolis; Peter M Nilsson; Luis Miguel Ruilope; Roland E Schmieder; Per Anton Sirnes; Peter Sleight; Margus Viigimaa; Bernard Waeber; Faiez Zannad; Josep Redon; Anna Dominiczak; Krzysztof Narkiewicz; Peter M Nilsson; Michel Burnier; Margus Viigimaa; Ettore Ambrosioni; Mark Caufield; Antonio Coca; Michael Hecht Olsen; Roland E Schmieder; Costas Tsioufis; Philippe van de Borne; Jose Luis Zamorano; Stephan Achenbach; Helmut Baumgartner; Jeroen J Bax; Héctor Bueno; Veronica Dean; Christi Deaton; Cetin Erol; Robert Fagard; Roberto Ferrari; David Hasdai; Arno W Hoes; Paulus Kirchhof; Juhani Knuuti; Philippe Kolh; Patrizio Lancellotti; Ales Linhart; Petros Nihoyannopoulos; Massimo F Piepoli; Piotr Ponikowski; Per Anton Sirnes; Juan Luis Tamargo; Michal Tendera; Adam Torbicki; William Wijns; Stephan Windecker; Denis L Clement; Antonio Coca; Thierry C Gillebert; Michal Tendera; Enrico Agabiti Rosei; Ettore Ambrosioni; Stefan D Anker; Johann Bauersachs; Jana Brguljan Hitij; Mark Caulfield; Marc De Buyzere; Sabina De Geest; Geneviève Anne Derumeaux; Serap Erdine; Csaba Farsang; Christian Funck-Brentano; Vjekoslav Gerc; Giuseppe Germano; Stephan Gielen; Herman Haller; Arno W Hoes; Jens Jordan; Thomas Kahan; Michel Komajda; Dragan Lovic; Heiko Mahrholdt; Michael Hecht Olsen; Jan Ostergren; Gianfranco Parati; Joep Perk; Jorge Polonia; Bogdan A Popescu; Zeljko Reiner; Lars Rydén; Yuriy Sirenko; Alice Stanton; Harry Struijker-Boudier; Costas Tsioufis; Philippe van de Borne; Charalambos Vlachopoulos; Massimo Volpe; David A Wood Journal: Eur Heart J Date: 2013-06-14 Impact factor: 29.983