Nlrp3 Deficiency Alleviates Angiotensin II-Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction.
Nlrp3 Deficiency Alleviates Angiotensin II-Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction.
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Nlrp3 缺陷通过抑制线粒体功能障碍减轻血管紧张素 II 诱发的心肌病
DOI：
10.1155/2021/6679100
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发表时间：
2021
影响因子：
--
通讯作者：
Sun T
中科院分区：
文献类型：
--
作者：
Chen Y;Zeng M;Zhang Y;Guo H;Ding W;Sun T
炎症被认为是血管紧张素II- (Ang II-)诱导的心肌肥大和相关心肌病发病和进展的关键因素。作为炎症的重要介质，Nlrp3炎症小体在Ang ii诱导的心肌病中的作用尚不清楚。本研究旨在确定Nlrp3炎性体激活及其下游途径是否参与Ang ii诱导的心肌病。我们在野生型和Nlrp3−/−小鼠中建立了Ang II输注模型，以确定Nlrp3对心功能的贡献。采用马松三色染色、实时荧光定量PCR和TUNEL法检测心脏纤维化；超声心动图评估心功能。采用Western blotting和酶联免疫吸附法检测Nlrp3炎性体活化及相关下游细胞因子；透射电镜和实时荧光定量PCR检测线粒体功能障碍。我们发现注入Ang ii的小鼠心功能受损，表现为心脏纤维化、细胞凋亡、炎症和左心室功能障碍增加。然而，在Nlrp3基因缺失的小鼠中，这些改变明显减轻。此外，与细胞因子IL-1β和IL-18相比，注入Ang ii的小鼠Nlrp3炎性体活性增加，活性氧增加，线粒体异常，mtDNA拷贝数和ATP合成酶活性降低。这些分子和病理改变在Nlrp3缺陷小鼠中也有所减弱。综上所述，Nlrp3炎症小体诱导的线粒体功能障碍参与了Ang ii诱导的心肌病。Nlrp3基因缺失可减轻线粒体异常、心脏炎症、氧化应激和纤维化，从而减轻心功能障碍和肥厚。靶向Nlrp3炎性体和/或线粒体可能是治疗angii诱导的心脏病的一种方法。
Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3−/− mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson's trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.
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作者：
Chin LH;Hsu YJ;Hsu SC;Chen YH;Chang YL;Huang SM;Tsai CS;Lin CY
通讯作者：
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