A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

Watanabe, Ryoji; Suzuki, Jun; Wakayama, Kouji; Maejima, Yasuhiro; Shimamura, Munehisa; Kuroda, Hiroshi; Nakagami, Hironori; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Morishita, Ryuichi; Komuro, Issei; Isobe, Mitsuaki

doi:10.1038/srep43920

Cited by 28 publications

(17 citation statements)

References 48 publications

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“…Mixtures of synthetic peptides derived from cat allergen epitopes have been successfully used to induce tolerance in clinical phase 2 tests ( 62 ). A peptide vaccine targeting angiotensin II was recently developed as a novel treatment for hypertension and the prevention of heart failure ( 63 ). Applications of immunodominant-epitope-based cancer vaccines combined with other strategies have significantly enhanced the specificity and safety of T-cell responses targeting to tumors ( 64 – 68 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

et al. 2017

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Hantaan virus (HTNV) infections can cause severe hemorrhagic fever with renal syndrome (HFRS) in humans, which is associated with high fatality rates. Cytotoxic T cell (CTL) responses contribute to virus elimination; however, to date, HLA class I allele-restricted HTNV glycoprotein (GP) epitopes recognized by CTLs have not been reported, limiting our understanding of CTL responses against HTNV infection in humans. In this study, 34 HTNV GP nine-mer epitopes that may bind to HLA-A*0201 molecules were predicted using the BIMAS and SYFPEITHI database. Seven of the epitopes were demonstrated to bind to HLA-A*0201 molecules with high affinity via the T2 cell binding assay and were successfully used to synthesize peptide/HLA-A*0201 tetramers. The results of tetramer staining showed that the frequencies of each epitope-specific CTL were higher in patients with milder HFRS, which indicated that the epitopes may induce protective CTL responses after HTNV infection. IFN-γ-enzyme-linked immunospot analysis further confirmed the immunoreactivity of epitopes by eliciting epitope-specific IFN-γ-producing CTL responses. In an HTNV challenge trial, significant inhibition of HTNV replication characterized by lower levels of antigens and RNA loads was observed in major target organs (liver, spleen, and kidneys) of HLA-A2.1/Kb transgenic mice pre-vaccinated with nonapeptides VV9 (aa8–aa16, VMASLVWPV), SL9 (aa996–aa1004, SLTECPTFL) and LL9 (aa358–aa366, LIWTGMIDL). Importantly, LL9 exhibited the best ability to induce protective CTL responses and showed a prominent effect on the kidneys, potentially preventing kidney injury after HTNV infection. Taken together, our results highlight that HTNV GP-derived HLA-A*0201-restricted epitopes could elicit protective CTL responses against the virus, and that epitope LL9 functions as an immunodominant protective epitope that may advance the design of safe and effective CTL-based HTNV peptide vaccines for humans.

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Section: Discussionmentioning

confidence: 99%

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

et al. 2017

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“…These effects of Ang II are correlated with the pathophysiology of MI. MI induces morphological changes called remodeling, which leads to heart failure accompanied by infarct area extension and thinning and compensatory hypertrophy of the non-infarcted myocardium [ 37 ]. Ang II-induced reactions may further damage the myocardium and accelerate post-MI remodeling [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Xinji′erkang on myocardial infarction induced cardiac injury in mice

Zhang

Wang

et al. 2017

BMC Complement Altern Med

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BackgroundMyocardial infarction (MI) is a major risk factor responsible for morbidity and mortality. Xinji′erkang (XJEK) has been clinically used as an effective medication in the treatment of coronary heart disease and myocarditis. The purpose of this study was to investigate the cardioprotective effect of Xinji′erkang on MI mice.MethodsForty male mice were randomly assigned into four groups as follows (n = 10): sham, model, MI with administration of XJEK and fosinopril for four weeks. At the end of studies, hemodynamic parameters and electrocardiography (ECG) were recorded. Heart and body mass were measured and heart weight/body weight (HW/BW) ratio was calculated as index of hypertrophy. The hypertrophy of heart and aorta was examined using the hematoxylin and eosin (HE) staining, and the collagen deposition was evaluated using Van Gieson (VG) staining. Serum nitric oxide level (NO), superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were assayed by colorimetric analysis. The expressions of endothelial NO synthetase (eNOS) expression in serum and cardiac tissues were determined using ELISA assay and immunohistochemistry. Angiotensin II (Ang II) in serum and cardiac tissues was measured using ELISA assay. Besides, tumor necrosis factor-α (TNF-α), interleukin1β (IL-1β) and interleukin10 (IL-10) were observed in cardiac tissues with ELISA assay as well.ResultsThe administration of XJEK significantly improved cardiac dysfunction and abnormal ECG with reduced HW/BW ratio and ameliorated cardiomyocyte hypertrophy and collagen deposition compared to MI, which was partly due to the decreased SOD and increased MDA in serum. Moreover, XJEK treatment also improved endothelial dysfunction (ED) with not only enhanced eNOS activities in serum and cardiac tissues and elevated NO levels in serum, but also decreased Ang II content in serum and cardiac tissues. Finally, protein expressions of pro-inflammation cytokines, TNF-α and IL-1β in the cardiac tissues with XJEK treatment were significantly decreased compared to model. On the contrary, IL-10, an anti-inflammatory cytokine concentrated in cardiac tissues was significantly enhanced compared to model.ConclusionXinji′erkang exerts cardioprotective effect on myocardial infarction in mice, which may be due to the improvement of endothelial dysfunction and the reduction of oxidative stress and inflammation response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1846-5) contains supplementary material, which is available to authorized users.

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“…The present study concluded that the Ang II-KLH vaccine diminished the cardiac remodeling that results in heart failure, improving cardiac function and suppressing adverse pathological changes in a rat model of myocardial infarction. In regard to the safety of the Ang II-KLH vaccine, no visible pathological changes were observed in various organs (heart, lung, liver, spleen, and kidney) and did not affect the levels of serum cystatin C, plasma brain natriuretic peptide-45, and serum albumin which reflect renal, cardiac, and hepatic function, respectively [27].…”

Section: Angiotensin IImentioning

confidence: 94%

Vaccines against components of the renin–angiotensin system

et al. 2020

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Even though effective drugs for treating hypertension are available, a great percentage of patients have inadequate control of their blood pressure. Unwanted side effects and inappropriate oral drug adherence are important factors that contribute to the global problem of uncontrolled hypertension. Vaccination could provide a revolutionary therapy with long-lasting effects, increasing patient compliance and therefore better control of high blood pressure. Nowadays, current immunization approaches against hypertension target renin, angiotensin I, angiotensin II, and angiotensin II type 1 receptor, key elements of the renin-angiotensin system. This article reviews the different vaccination attempts with proteins and peptides against the different molecules of the renin-angiotensin system in the last two decades, safety issues, and other novel prospects biomarkers in hypertension, and summarizes the potential of this immunomodulatory approach in clinical practice.

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A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

Cited by 28 publications

References 48 publications

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

Protective effects of Xinji′erkang on myocardial infarction induced cardiac injury in mice

Vaccines against components of the renin–angiotensin system

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