Decrease in Blood Pressure and Regression of Cardiovascular Complications by Angiotensin II Vaccine in Mice

Abstract

Vaccines have been recently developed to treat various diseases such as cancer, rheumatoid arthritis and Alzheimer’s disease in addition to infectious diseases. However, before use in the clinical setting, vaccines targeting self-antigens must be demonstrated to be effective and safe, evoking an adequate humoral immune response from B cells while avoiding T cell activation in response to self. Although the vaccine targeting angiotensin II (Ang II) is efficient in rodents and humans, little is known regarding the immunological activation and safety of the vaccine. In this study, we evaluated the efficiency and safety of an Ang II peptide vaccine in mice. Immunization with Ang II conjugated to keyhole limpet hemocyanin (KLH) successfully induced the production of anti-Ang II antibody, which blocked Ang II signaling in human aortic smooth muscle cells. However, Ang II itself did not activate T cells, as assessed by the proliferation and lymphokine production of T cells in immunized mice, whereas KLH activated T cells. In an Ang II-infused model, the non-immunized mice showed high blood pressure (BP), whereas the immunized mice (Ang II-KLH) showed a significant decrease in systolic BP, accompanied by significant reductions in cardiac hypertrophy and fibrosis. Importantly, anti-Ang II antibody titer was not elevated even after the administration of large amounts of Ang II, indicating that Ang II itself boosted antibody production, most likely due to less activation of T cells. In addition, no accumulation of inflammatory cells was observed in immunized mice, because endogenous Ang II would not activate T cells after immunization with Ang II-KLH. Taken together, these data indicate that vaccines targeting Ang II might be effective to decrease high BP and prevent cardiovascular complications without severe side effects.

Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress

“…40 However, it is unlikely because no effects on BP were observed in the present study. This finding is compatible with the previous reports showing no BP lowering effects of Ang II peptide vaccine in normotensive mice, 10 despite the reduction of BP in hypertensive rats. 25 Therefore, the therapeutic efficacy of Ang II peptide vaccine for ischemic injury without a concomitant effect on BP seems to be a promising preventive approach for normotensive as well as hypertensive patients.…”

“…Consistent with a previous report stating that BP was not altered in normotensive Ang II peptide vaccinated mice, 10 To investigate whether vaccination affected the brain Ang II concentration, the concentration of Ang II in the brain was examined. However, no significant differences were observed between the groups ( Figure 1C).…”

“…Although we could not examine whether the effects were preserved >15 days because of the limitation of the stroke model, the preventive effects of Ang II peptide vaccine may have lasted up to several months because we observed the continuing existence of anti-Ang II antibody in serum at least ≤3 months after immunization. 10 In addition, the previous clinical study using Ang II vaccine demonstrated the reversible antibody response against Ang II, with a half-life of ≈4 months after immunization. 20 In clinical settings, this possible long-lasting efficacy would be promising compared with the standard inhibitor of the RAS because poor adherence to secondary preventive medication owing to poststroke dementia or other neurological deficits is a major risk of the recurrence of ischemic stroke.…”

“…9 In addition, economic burden is a concern pertaining to long-term treatment. To alleviate the compliance concerns and improve preventive outcomes, we assessed the effects of the recently developed Ang II peptide vaccine 10 in preventing ischemic stroke.…”

“…19 Therefore, here we focused on developing a vaccine against RAS because the inhibition of RAS by ACE-Is and ARBs has been widely accepted as a safe and effective treatment for the primary and secondary prevention of ischemic stroke. Because previous reports demonstrated that Ang II peptide vaccine or Ang II DNA vaccine was free from anti-Ang II autoimmune response and exerted a long-lasting antihypertensive effect in animal experiments 10,20 and human clinical trials, 20 Ang II peptide vaccine is a promising therapeutic modality for the treatment of hypertension. However, it is still unclear whether the protective effect of Ang II peptide vaccine against ischemic damages is over and above its antihypertensive effects.…”