Miličić Stanić Branka, Maddox Sydney, de Souza Aline M A, Wu Xie, Mehranfard Danial, Ji Hong, Speth Robert C, Sandberg Kathryn
Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, District of Columbia.
Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida.
Am J Physiol Regul Integr Comp Physiol. 2021 Jun 1;320(6):R925-R937. doi: 10.1152/ajpregu.00356.2020. Epub 2021 Apr 13.
Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.
在全球范围内，包括美国，男性感染新冠病毒（COVID-19）的后果比女性更严重。导致COVID-19大流行的病毒严重急性呼吸综合征冠状病毒2（SARS-CoV-2）利用血管紧张素转换酶2（ACE2）进入细胞。ACE2是肾素-血管紧张素系统（RAS）的成员，在对抗血管紧张素1型受体介导的有害作用中发挥重要作用。因此，我们对Ovid MEDLINE和Embase数据库进行了检索，以查找2000年（ACE2被发现的年份）至2020年12月31日期间调查性别这一生物学变量对ACE2表达和调控影响的基础科学研究。在2131篇出版物中，我们确定了853篇关于ACE2的原创研究文章，这些研究是在原代细胞、组织和/或除人类以外的整个哺乳动物中进行的。这些引用了动物性别的研究中，大多数（68.7%）是在雄性动物中进行的，而11.2%仅在雌性动物中进行；9.26%对两性之间的ACE2进行了比较，而10.8%未报告所使用动物的性别。一般研究结果是，性别差异具有组织特异性，并且在存在时取决于性腺状态。在模拟与更严重的COVID-19后果相关的合并症（包括高血压、肥胖以及肾脏和心血管疾病）的实验条件下，两性的肾脏、心脏和脂肪组织中的ACE2都会增加；然而，ACE2蛋白通常在雄性中更高。对基因敲除小鼠的研究表明，ACE2在保护雌性免受高血压方面比雄性发挥更大作用。在ACE2研究中研究性别这一生物学变量为发现涉及RAS功能障碍的疾病提供了机会，并将阐明COVID-19严重程度方面的性别差异。
