The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies
The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies
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DOI：
10.1007/s11739-020-02364-6
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发表时间：
2020-05-19
影响因子：
4.6
通讯作者：
Lombardo, Michele
中科院分区：
文献类型：
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作者：
Albini, Adriana;Di Guardo, Giovanni;Lombardo, Michele
SARS-CoV-2的特征是一种刺突蛋白，允许病毒与血管紧张素转换酶（ACE）-2结合，ACE-2作为病毒受体，在几种肺和肺外细胞类型（包括心脏、肾脏、肠和内皮细胞）的表面表达。有证据表明，内皮细胞也被SARS-COV-2感染，随后发生系统性血管炎、血栓栓塞和弥散性血管内凝血。这些影响与“细胞因子风暴”一起参与了更差的预后。在临床实践中，血管紧张素转换酶抑制剂（ACE-Is）和血管紧张素II受体阻滞剂（ARB）被广泛用于治疗高血压和其他心血管疾病。在体内研究中，ACE-Is和ARB似乎矛盾地增加ACE-2表达，这可能有利于SARS-CoV-2感染宿主细胞和组织。相比之下，在接受ACE-Is和ARB治疗的患者中，肾脏和心脏组织中的ACE-2在mRNA和蛋白水平上显示下调。然而，已经声称ARB和ACE-Is都可能在SARS-CoV-2感染患者的临床过程中产生潜在的有用性。正如在中国检测到的以及意大利流行病学情况所证实的，COVID-19死亡患者中最常见的合并症是高血压、糖尿病和心血管疾病。患有心血管合并症的老年COVID-19患者表现出更严重的临床病程和更差的预后，其中许多人还接受ARB或ACE-Is治疗。另一个混杂因素是吸烟，据报道，吸烟会增加实验模型和人体中ACE-2的表达。性别也发挥了作用，X染色体携带ACE-2编码基因，这是女性患者死亡率较低的可能解释之一。病毒进入还取决于TMPRSS 2蛋白酶活性，一种雄激素依赖性酶。尽管实验动物研究具有相关性，但为了全面解决ACE-Is和ARB对接受这些抗高血压药物治疗的COVID-19感染患者的临床过程的潜在危害或益处，我们需要进行随机人体研究。我们认为需要进行足够的前瞻性研究，以回答以下对心血管、内科和急诊医学至关重要的问题：ACE-Is和ARB对感染或疾病进程的影响是否相似或不同？这些影响对年龄较大的COVID-19患者是否危险、中性甚至有用？它们是否作用于多种细胞类型？由于ACE-Is和ARB具有不同的分子靶点，因此在接受这两种药物治疗的患者中，SARS-CoV-2感染的临床过程也可能不同。目前，从试验中获得的详细数据不足。
SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the "cytokine storm" are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host's cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.