Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction
Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction
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肝脏血管紧张素原的丧失可减轻脓毒症引起的心肌功能障碍
DOI：
10.1161/circresaha.120.318075
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发表时间：
2021-08-20
影响因子：
20.1
通讯作者：
Wang, Jian'an
中科院分区：
文献类型：
--
作者：
Rong, Jiabing;Tao, Xinran;Wang, Jian'an
补充数字内容可在文本中找到。原理：肾素-血管紧张素系统是一个复杂的调节网络，维持正常的生理功能。肾素-血管紧张素系统在脓毒症诱导的心肌功能障碍（SIMD）中的作用还不清楚。AGT（血管紧张素原）是肾素-血管紧张素系统的独特前体，并产生所有的血管紧张素肽。AGT在SIMD发展中的作用和机制尚未明确。目的：探讨AGT在SIMD发病中的作用及其机制。方法和结果：腹腔内注射脂多糖或盲肠结扎和穿刺显着增加AGT在肝脏，心脏和血浆中的丰度。肝细胞源性AGT的缺乏，而不是心肌细胞源性AGT，减轻小鼠脓毒性心功能不全，延长生存时间。进一步的研究表明，肝细胞来源的AGT对SIMD的影响部分与循环中血管紧张素II（血管紧张素II）的产生有关。此外，肝细胞来源的AGT被心脏成纤维细胞中的LRP 1（LDL [低密度脂蛋白]受体相关蛋白1）内化，随后通过Ang II非依赖性途径激活NLRP 3（NLR家族pyrin domain containing 3）炎性体，最终通过抑制心肌细胞中SERCA 2a（肌浆网Ca[2+]-ATP酶2a）丰度促进SIMD。结论：肝细胞源性AGT通过Ang II依赖性和非依赖性途径促进SIMD。我们确定了一个肝心轴AGT调节SIMD的发展。我们的研究可能为SIMD提供一个潜在的新的治疗靶点。
Supplemental Digital Content is available in the text. Rationale: The renin-angiotensin system is a complex regulatory network that maintains normal physiological functions. The role of the renin-angiotensin system in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in the development of SIMD have not been defined. Objective: To determine a role of AGT in SIMD and investigate the underlying mechanisms. Methods and Results: Either intraperitoneal injection of lipopolysaccharide or cecal ligation and puncture significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT, rather than cardiomyocyte-derived AGT, alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepatocyte-derived AGT on SIMD were partially associated with augmented Ang II (angiotensin II) production in circulation. In addition, hepatocyte-derived AGT was internalized by LRP1 (LDL [low-density lipoprotein] receptor-related protein 1) in cardiac fibroblasts and subsequently activated NLRP3 (NLR family pyrin domain-containing 3) inflammasome via an Ang II–independent pathway, ultimately promoting SIMD by suppressing SERCA2a (sarco[endo]plasmic reticulum Ca[2+]-ATPase 2a) abundances in cardiomyocytes. Conclusions: Hepatocyte-derived AGT promoted SIMD via both Ang II–dependent and Ang II–independent pathways. We identified a liver-heart axis by which AGT regulated development of SIMD. Our study may provide a potential novel therapeutic target for SIMD.