Blocking FcγRIIB in Smooth Muscle Cells Reduces Hypertension
| Autor: | Yi Fu, Zhu Jie Cao, Xuan Zou, Chen Yan, Cui-Liu Hou, Ling Jin, Jun Cai, Wei Kong, Wei Peng Ge, Tian tian Zhang, Hongmei Zhao, Jing Wang, Xiaomin Song |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Physiology Myocytes Smooth Muscle Blood Pressure Receptors angiotensin Vascular Remodeling Antibodies Muscle Smooth Vascular Receptor Angiotensin Type 1 Muscle hypertrophy Smooth muscle Medicine Animals Humans Extracellular Signal-Regulated MAP Kinases Antihypertensive Agents Mice Knockout biology Blocking (radio) business.industry Receptors IgG Middle Aged Acquired immune system Rats Mice Inbred C57BL Disease Models Animal Chronic disease HEK293 Cells Case-Control Studies Immunoglobulin G Immunology Hypertension biology.protein Female Antibody Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | Circulation research. 129(2) |
| ISSN: | 1524-4571 |
| Popis: | Rationale: Hypertension is a common chronic disease, and its prevalence is increasing. Immunoglobulins play crucial roles in adaptive immune response and have been implicated in the pathogenesis of hypertension. However, which immunoglobulins and receptors as well as underlying mechanisms participating in hypertension remains unknown. We found that IgG is significantly increased in hypertensive patients, suggesting a potential association between IgG signaling and hypertension. Objective: This study is aimed to investigate the role and underlying mechanism of IgG and its receptor in hypertension. Methods and Results: We showed that serum IgG and the expression of IgG receptor FcγR (Fcγ receptor) IIB in vessel were significantly increased in hypertensive mice. Blockade of FcγRIIB function significantly reduced Ang II (angiotensin II)–induced vascular remodeling and hypertension in mice with genetic ablation of FcγRIIB or with systemic anti-FcγRIIB antibody treatment in mice. The studies with bone marrow transplantation approach or smooth muscle cell (SMC)–specific FcγRIIB ablation revealed that the role of FcγRIIB in vascular remodeling and hypertension is largely dependent on SMCs but not bone marrow–derived cells. Interestingly, we found that FcγRIIB expressed in SMCs is important in SMC-dependent vascular contraction ex vivo, as well as Ang II–induced SMC hypertrophy and matrix protein expression in vitro. Mechanistic studies further revealed that IgG stimulates FcγRIIB association with AT1R (Ang II type 1 receptor) in SMCs and inhibits AT1R internalization, thus increasing the cell membrane AT1R level. Furthermore, FcγRIIB-mediated regulation of AT1R internalization is critical for Ang II–induced SMC ERK (extracellular signal-regulated kinase) 1/2 activation and hypertrophy, as well as for Ang II–induced arterial contraction. Conclusions: Taken together, our findings indicate that IgG/FcγRIIB contributes to vascular remodeling and hypertension, at least partially through suppressing AT1R internalization in SMCs. Our findings also suggest that FcγRIIB may represent an innovative therapeutic target for hypertension, especially for patients with autoimmune diseases. |
| Databáze: | OpenAIRE |
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