S-39-2: EFFECTS OF RAS INHIBITORS ON TISSUE ACE2 EXPRESSION IN ANIMAL MODELS
S-39-2: EFFECTS OF RAS INHIBITORS ON TISSUE ACE2 EXPRESSION IN ANIMAL MODELS
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S-39-2：RAS 抑制剂对动物模型中组织 ACE2 表达的影响
DOI：
10.1097/01.hjh.0000913576.19713.f8
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发表时间：
2023
影响因子：
4.9
通讯作者：
Kai Mamiko
中科院分区：
文献类型：
--
作者：
Kai Hisashi;Kai Mamiko
血管紧张素转换酶2(ACE2)对肾素-血管紧张素系统(RAS)过度激活引起的器官损伤具有保护作用。此外，ACE2还作为SARS-CoV-2进入宿主靶细胞的受体发挥作用。根据有限数量的文献报道，RAS抑制剂在动物模型中诱导心脏或肾脏血管紧张素转换酶2表达上调，已引起关注，即RAS抑制剂可能加重SARS-CoV-2感染和新冠肺炎的严重程度。因此，我们采用系统评价的标准检索策略，对RAS抑制剂在健康动物和疾病动物模型中对心脏、血管、肾脏和肺组织中ACE2基因表达的影响进行了全面综述。我们确定了88篇符合条件的文章，包括167个实验。在RAS抑制剂治疗的健康动物中，37个实验中只有3个(心脏2，肾脏1)的ACE2表达超过对照的两倍(过度表达)，而其他动物的心脏、动脉、肾脏、肺和其他器官没有/边缘变化。在102个疾病模型(130个实验)中，16个模型(18个实验)的基线ACE2过表达，28个模型(40个实验)的ACE2表达水平低于对照水平的一半，51个模型(74个实验)保持不变/边际变化。仅有7个实验通过NO/边缘改变诱导ACE2过度表达，其中4个(心肌梗死2个，心力衰竭1个，糖尿病肾病1个)在类似条件下没有得到其他实验的支持。在36个实验中，RAS抑制剂逆转或阻止了疾病诱导的抑制，没有产生任何/边际变化。因此，在健康的动物和疾病模型中，ACE2的过度表达是RAS抑制剂治疗的罕见后果。未来的研究应阐明在疾病模型中逆转或预防RAS抑制剂诱导的ACE2抑制的病理生理学意义。
Angiotensin-converting enzyme 2 (ACE2) protects against organ damages by overactivated renin-angiotensin system (RAS). Also, ACE2 exerts a role as the receptors for SARS-CoV-2 to enter host target cells. Based on limited number of articles reporting that RAS inhibitors induced upregulation of cardiac or renal ACE2 in animal models, concern have arisen that RAS inhibitors may aggravate SARS-CoV-2 infection and COVID-19 severity. Therefore, we performed a comprehensive review by applying the standard searching strategy for systematic reviews to investigate the effects of RAS inhibitors on cardiac, vascular, renal and pulmonary mRNA/protein ACE2 expression in healthy animals and disease animal models. We identified 88 eligible articles including 167 experiments. In RAS inhibitors-treated healthy animals, only 3 (heart 2, kidneys 1) of 37 experiments showed ACE2 expression greater than twice of the control (overexpression) whereas others showed no/marginal change in the heart, arteries, kidneys, lungs, and other organs. Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments), less than half the control level (repression) in 28 models (40 experiments) and remained no/marginal change in 51 models (74 experiments). RAS inhibitors induced ACE2 overexpression from no/marginal change levels in only 7 experiments, 4 (myocardial infarction 2, heart failure 1, diabetic nephropathy 1) of which were not supported by other experiments under similar conditions. In 36 experiments, RAS inhibitors reversed or prevented disease-induced repression, yielding no/marginal change. Thus, ACE2 overexpression is a rare consequence of RAS inhibitors treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of reversal or prevention of ACE2 repression induced by RAS inhibitors in disease models.