Nor Rashid Nurshamimi, Amrani Lina, Alwan Abdullah, Mohamed Zulqarnain, Yusof Rohana, Rothan Hussin
Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
Mol Biotechnol. 2024 Sep 13. doi: 10.1007/s12033-024-01277-5.
Angiotensin-converting enzyme-2 (ACE2) downregulation represents a detrimental factor in people with a baseline ACE2 deficiency associated with older age, hypertension, diabetes, and cardiovascular diseases. Human coronaviruses, including HCoV-NL63, SARS-CoV-1, and SARS CoV-2 infect target cells via binding of viral spike (S) glycoprotein to the ACE2, resulting in ACE2 downregulation through yet unidentified mechanisms. This downregulation disrupts the enzymatic activity of ACE2, essential in protecting against organ injury by cleaving and disposing of Angiotensin-II (Ang II), leading to the formation of Ang 1-7, thereby exacerbating the accumulation of Ang II. This accumulation activates the Angiotensin II type 1 receptor (AT1R) receptor, leading to leukocyte recruitment and increased proinflammatory cytokines, contributing to organ injury. The biological impacts and underlying mechanisms of ACE2 downregulation during SARS-CoV-2 infection have not been well defined. Therefore, there is an urgent need to establish a solid theoretical and experimental understanding of the mechanisms of ACE2 downregulation during SARS-CoV-2 entry and replication in the host cells. This review aims to discuss the physiological impact of ACE2 downregulation during coronavirus infection, the relationship between ACE2 decline and virus pathogenicity, and the possible mechanisms of ACE2 degradation, along with the therapeutic approaches.
血管紧张素转换酶2（ACE2）下调是老年、高血压、糖尿病和心血管疾病相关基线ACE2缺乏人群的一个有害因素。包括HCoV-NL63、SARS-CoV-1和SARS-CoV-2在内的人类冠状病毒通过病毒刺突（S）糖蛋白与ACE2结合感染靶细胞，通过尚未明确的机制导致ACE2下调。这种下调破坏了ACE2的酶活性，而ACE2通过切割和处理血管紧张素II（Ang II）来预防器官损伤至关重要，导致血管紧张素1-7的形成，从而加剧Ang II的积累。这种积累激活血管紧张素II 1型受体（AT1R），导致白细胞募集和促炎细胞因子增加，促成器官损伤。SARS-CoV-2感染期间ACE2下调的生物学影响和潜在机制尚未明确。因此，迫切需要对SARS-CoV-2进入和在宿主细胞中复制期间ACE2下调的机制建立扎实的理论和实验理解。本综述旨在讨论冠状病毒感染期间ACE2下调的生理影响、ACE2下降与病毒致病性之间的关系、ACE2降解的可能机制以及治疗方法。
