Immunization with plasmids encoding M2 acetylcholine muscarinic receptor epitopes impairs cardiac function in mice and induces autophagy in the myocardium

Ribeiro, Karla Consort; Campelo, Roberto Perez; Rodrigues, Daniela del Rosário Flores; Mattos, Elisabete C.; Brandão, Izaíra Trincani; Silva, Célio Lopes; Martinez, Camila Guerra; Kurtenbach, Eleonora

doi:10.1080/08916934.2018.1514389

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…In contrast to M1 macrophages, M2 macrophages are involved in inflammation suppression, tissue repair and angiogenesis (Ribeiro et al, 2018). Therefore, the effect of QSG on differentiation of M2 macrophages was further investigated.…”

Section: Resultsmentioning

confidence: 99%

Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages

et al. 2019

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Macrophages play a pivotal role in myocardial remodeling (MR) process which could eventually lead to heart failure. Splenic monocytes could be mobilized and recruited under inflammatory conditions and differentiated into different types of macrophages in heart tissues. Inflammatory M1 macrophages could aggravate tissue damage whereas M2 macrophages could promote angiogenesis and tissue repair process. Unbalanced ratio of M1/M2 macrophages may eventually lead to adverse remodeling. Therefore, regulating differentiation and activities of macrophages are potential strategies for the management of myocardial remodeling. Qishen Granule (QSG) is an effective Chinese medicine for treating heart failure. Our previous studies demonstrated that QSG could inhibit myocardial fibrosis through regulating secretion of cytokines and activation of macrophages. However, the detailed effects of QSG on had not been elucidated yet. In this study, we aimed to explore the effect of QSG on the release of splenic monocytes, the recruitment of monocytes into heart tissues and the differentiation of macrophages under ischemic conditions. Our results showed that QSG could suppress the release of monocytes from the spleen and recruitment of monocytes to heart tissues via inhibiting splenic angiotensin (Ang) II/AT1-cardiac monocyte chemotactic protein (MCP)-1/CC chemokine receptor 2 (CCR2) pathway. The anti-fibrotic effect of QSG was exerted by inhibiting M1 macrophage-activated transforming growth factor (TGF)-β1/Smad3 pathway. Meanwhile, QSG could promote angiogenesis by promoting differentiation of M1 macrophages into M2 macrophages. Our results suggest that compounds of Chinese medicine have synergistic effects on cardiac and splenic organs through regulating differentiation of monocytes/macrophages in inhibiting myocardial remodeling.

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Section: Resultsmentioning

confidence: 99%

Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages

et al. 2019

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“…Gimenez et al [16] have attempted to conduct mouse immunization by using plasmid DNA encoding entire M2 receptor proteins, which can lead to contractile dysfunction and cardiac remodeling. Further study revealed some ultrastructural alterations suggesting autophagy and mitophagy in mice immunized with a plasmid encoding an M2 receptor epitope, suggesting novel roles for the anti-M2-R [17]. Our previous study showed that anti-M2-R not only existed in IDCM patients, but also in heart failure caused by different cardiac diseases, such as ischemic cardiomyopathy, hypertensive heart disease, and rheumatic valvular heart disease.…”

Section: Anti-m2-r and Heart Failurementioning

confidence: 89%

Association of autoantibodies against the M2-muscarinic receptor with long-term outcomes in peripartum cardiomyopathy patients: A 5-year prospective study

Wang

Hou

et al. 2019

Journal of Cardiology

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Background: Peripartum cardiomyopathy (PPCM) is characterized by heart failure. Our previous study found that autoantibodies against the M2-muscarinic receptor (anti-M2-R) are increased in PPCM patients. We aimed to evaluate the association of anti-M2-R on prognosis of PPCM patients with standard treatment. Methods: Synthetic peptides corresponding to the M2 receptor served as the target antigens in an enzyme-linked immunosorbent assay experiment. They were used to screen the sera of 80 PPCM patients, who were separated into anti-M2-R-negative and positive groups according to their anti-M2-R reactivity. Clinical assessment and echocardiography examination were performed at baseline and after 5 years with a standard treatment regimen. The endpoint events were compared after 5 years of follow-up. Results: There were 76 PPCM patients who completed the final data analysis, including 36 in the anti-M2-R (+) group and 40 in the anti-M2-R (À) group. Both groups showed improvement in the left ventricular end-diastolic and end-systolic dimensions and the ejection fraction with standard treatment regimens for 5 years (all p < 0.001). Patients in the anti-M2-R (À) group had greater tolerance and were more rapidly titrated to metoprolol, and they had better improvement in cardiac function than patients in the anti-M2-R (+) group (p < 0.05). Patients in the anti-M2-R (À) group had a marked decrease in rehospitalization (p < 0.05), but not in all-cause mortality or cardiovascular mortality. Being positive for anti-M2-R increased the risk of PPCM (OR = 4.7, 95% CI 1.8-12.2, p = 0.002). Conclusions: PPCM patients, especially anti-M2-R (À) patients, have a relatively better prognosis than other patients. We posit that the presence of anti-M2-R may be involved in the pathogenesis of PPCM.

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“…Gimenez et al [15] have immunized mouse by using plasmid DNA encoding entire M2 receptor proteins, which leads to cardiac remodeling and contractile dysfunction. Ribeiro et al [16] found immunization with plasmids encoding M2 receptor epitopes impairs cardiac function in mice and induces autophagy in the myocardium, indicating novel roles for the anti-M2-R. Our previous study suggested anti-M2-R not only existed in IDCM patients, but also in HF caused by different causes, including PPCM. We posit that serum anti-M2-R may be related to cardiac structural and functional changes, which need further studies to clarify [3].…”

Section: Anti-m2-r and Ppcmmentioning

confidence: 86%

Effects of Autoantibody Against M2-Muscarinic Acetylcholine Receptor in Peripartum Cardiomyopathy Patients on Digoxin Additional to Standard Treatment

Ma¹,

Chen²,

Yue³

et al. 2021

Journal of the American College of Cardiology

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To evaluate the effects of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on digoxin additional to standard treatment in peripartum cardiomyopathy (PPCM) patients. MethodsPPCM patients, receiving digoxin and standard treatment regimen for HF, were enrolled between January 1998 and June 2020, who were separated into anti-M2-R negative (n = 59) or positive (n = 48) group according to the anti-M2-R reactivity. Echocardiography and serum digoxin concentration (SDC) were performed regularly. All-cause mortality, cardiovascular mortality and re-hospitalization for heart failure were compared. Results103 patients completed the nal data analysis, including 46 in the anti-M2-R (+) group and 57 in the anti-M2-R (-) group. Heart rate of the positive group was lower than that of the negative group at baseline (102.7 ± 6.1 vs. 96.0 ± 6.4, p < 0.001). The initial SDC of patients in the positive group was higher than that of patients in the negative group with the same dosage of digoxin (1.25 ± 0.45 vs. 0.78 ± 0.24 ng/mL, p < 0.001). Anti-M2-R (-) patients had better tolerance to metoprolol (38.4 ± 4.6 mg b.i.d. vs. 27.4 ± 5.0 mg b.i.d., p < 0.0001) and digoxin (0.12 ± 0.02 mg/day vs. 0.08 ± 0.04 mg/day, p < 0.0001). The improvement of heart function was obvious in the rst year, especially in the rst half. Furthermore, anti-M2-R (-) patients showed better improvement than that in anti-M2-R (+) patients. Re-hospitalization for heart failure was decreased in the negative group, but not of all-cause or cardiovascular mortality. ConclusionsAnti-M2-R maybe a predictor for vagus nerve overactivation and is associated with poor response to digoxin in PPCM patients.

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Immunization with plasmids encoding M2 acetylcholine muscarinic receptor epitopes impairs cardiac function in mice and induces autophagy in the myocardium

Cited by 7 publications

References 48 publications

Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages

Qishen Granule Improved Cardiac Remodeling via Balancing M1 and M2 Macrophages

Association of autoantibodies against the M2-muscarinic receptor with long-term outcomes in peripartum cardiomyopathy patients: A 5-year prospective study

Effects of Autoantibody Against M2-Muscarinic Acetylcholine Receptor in Peripartum Cardiomyopathy Patients on Digoxin Additional to Standard Treatment

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