The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotens
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CE - LETTER TO THE EDITOR
The SARS‑CoV‑2 receptor, ACE‑2, is expressed on many different cell types: implications for ACE‑inhibitor‑ and angiotensin II receptor blocker‑based antihypertensive therapies—reply Adriana Albini1 · Douglas McClain Noonan1,2 · Giuseppe Pelosi3,4 · Giovanni Di Guardo5 · Michele Lombardo6 Received: 27 June 2020 / Accepted: 6 July 2020 © Società Italiana di Medicina Interna (SIMI) 2020
Dear Editor, We read with great interest the comment by Dr. De Cauwer [1] in response to our Point of View [2]. He raises several interesting points. Chromosome X harbors the gene coding for angiotensin converting enzyme 2 (ACE-2) receptor, which allows SARSCoV-2 entry into host cells. This could partially explain, in turn, the increased mortality reported in males in comparison with females: indeed, deaths attributed to SARS-CoV-2 infection were significantly higher among male individuals, both in China and in Italy [2]. Males carrying rare ACE2-coding variants (polymorphisms) will express those variants in all ACE-2-expressing cells, whereas females will typically express those variants in a mosaic distribution, driven by early X-inactivation events. The aggregated prevalence of the aforementioned ACE-2 variants is supposed to be 3.9 per 1000 males and 8.5 per 1000 females [3]. If this holds true, it might indirectly suggest a protective role of ACE-2 overexpression in the clinical course of SARS-CoV-2 infection in female patients. The SARS virus in infected cells down-regulates the ACE-2, we mentioned this in our Point * Adriana Albini [email protected] 1
Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy
2
Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
3
Department of Oncology and Hemato‑Oncology, University of Milan, Milan, Italy
4
Inter‑Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy
5
University of Teramo, Faculty of Veterinary Medicine, 64100 Teramo, Italy
6
Cardiology Unit, San Giuseppe Hospital-MultiMedica, Milan, Italy
of View [2]. ACE-2 produces Ang (1–7) heptapeptide, an anti-inflammatory molecule. Zoonotic human beta-coronaviruses (SARS-CoV-1, MERS and SARS-CoV-2) have multiple strategies for proteolytic activation of spike (S) protein and viral entry, including cell surface transmembrane protease/serine (TMPRSS) proteases, endosomal cathepsins, and furin [2, 4]. The transmembrane protease serine 2 TMPRSS2, an androgendependent enzyme, acts in reinforcing the ACE-2 receptor activity in allowing cell entry to a number of viral pathogens as well as to SARS-CoV-2 as reported in our Point of View [2]. Moreover, the expression of TMPRSS2 on endothelial cells together with ACE-2 could account for the severity of SARS-CoV-2 infection via microthrombus formation beyond pro-inflammatory cytokines release causing a multiorgan failure alongside a disseminated intravascular coagulation [2]. The androgen receptor (AR) gene and ACE-2 both map to chromosome X and polymorphisms of these genes could result in diff
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