key: cord-1051903-88oevwih authors: Dhaundiyal, Ankit; Kumari, Puja; Jawalekar, Snehal Sainath; Chauhan, Gaurav; Kalra, Sourav; Navik, Umashanker title: Is highly expressed ACE 2 in pregnant women “a curse” in times of COVID-19 pandemic? date: 2020-10-28 journal: Life Sci DOI: 10.1016/j.lfs.2020.118676 sha: faa4affda990e69a85e7d47ae4c9ed55a6c0b777 doc_id: 1051903 cord_uid: 88oevwih Angiotensin-converting enzyme 2 (ACE 2) is a membrane-bound enzyme that cleaves angiotensin II (Ang II) into angiotensin (1–7). It also serves as an important binding site for SARS-CoV-2, thereby, facilitating viral entry into target host cells. ACE 2 is abundantly present in the intestine, kidney, heart, lungs, and fetal tissues. Fetal ACE 2 is involved in myocardium growth, lungs and brain development. ACE 2 is highly expressed in pregnant women to compensate preeclampsia by modulating angiotensin (1–7) which binds to the Mas receptor, having vasodilator action and maintain fluid homeostasis. There are reports available on Zika, H1N1 and SARS-CoV where these viruses have shown to produce fetal defects but very little is known about SARS-CoV-2 involvement in pregnancy, but it might have the potential to interact with fetal ACE 2 and enhance COVID-19 transmission to the fetus, leading to fetal morbidity and mortality. This review sheds light on a path of SARS-CoV-2 transmission risk in pregnancy and its possible link with fetal ACE 2. Angiotensin-converting enzyme (ACE) is an ectoenzyme with a molecular weight of 195 kDa, which plays a crucial role in the renin-angiotensin system (RAS) pathway. The ACE enzyme converts angiotensin I (Ang I), a decapeptide to angiotensin II (Ang II), an octapeptide that binds to the AT 1 receptor to induce vasoconstrictor response, which is a well-known target for the treatment of cardiovascular complications (Turner et al. , 2002 , Warner et al. , 2004 . ACE 2 is a type I transmembrane metallocarboxypeptidase, composed of a single HEXXH zinc-binding domain and is a homologue of ACE with 40% similarity. ACE 2 is able to hydrolyze angiotensin I (Ang I) to produce angiotensin (1-9) and inactivates potent vasoconstrictor Ang II to produce angiotensin-(1-7) (Ang I-7). The enzyme is able to cleave several peptides from other systems such as the kinin metabolites, neurotensin 1-13, apelin 13, dynorphin 1-13 (Vickers et al. , , systems which have high expression of ACE 2 (Li et al., 2020a , Navik et al. , 2020 , Taylor et al. , 2019 . Preeclampsia is a pregnancy complication characterized by high blood pressure and proteinuria and usually begins after 20 weeks of gestation. It is one of the foremost reasons for maternal and fetal morbidity and mortality (Merrill et al. , 2002) . Reports suggest that the levels of angiotensinogen, Ang II, and mineralocorticoids are increased in pregnancy and lead to preeclampsia (Levy et al., 2008 , Shah, 2005 . Further, to regulate this increased blood pressure, a compensatory increase in ACE 2 activity leads to the production of Ang (1-7) which causes vasodilation, reduces the production of aldosterone by acting on adrenal glomerulosa cells (Kalra et al. , 2013 , Marcus et al. , 2013 , Merrill et al., 2002 , Neves et al. , 2008 , Shefer et al. , 2016 . ACE 2 has an antihypertrophic activity that plays a pivotal role in cardiac tissue during the gestational period and may modulate myocardial tissue growth (Song et al. , 2012 , Yamamoto et al. , 2006 . Additionally, a report shows that ACE 2 is also involved in fetal brain and lung development in the gestation period (Song et al., 2012) . Experimental evidence shows that Murine coronavirus infects placenta and uterus in pregnancy/challenge of susceptible , availability of reports in literature regarding the vertical transmission of SARS-CoV-2 infection from mother to fetus has raised the concern for the potential interaction of ACE 2 with SARS-CoV-2 virus. In this review, we focus on the importance of the ACE 2 receptor in SARS-CoV-2 transmission from pregnant women to fetuses and neonates. SARS-CoV-2 is a positive-sense single-stranded RNA virus and causes respiratory illness. SARS-CoV-2 genome is identical to SARS-CoV (80%) and BatCoV RaTG13 (96%) (Zhou et al., 2020) . There are four major proteins in the structure of SARS-CoV; namely N protein (nucleocapsid), M protein (membrane), E protein (envelope), and S protein (spikes that lead to virus entry) (Chokkar et al. , 2019 , Liu et al. , 2014 , Masters, 2006 , Mortola and Roy, 2004 , Wang et al. , 2017 . N protein functions largely to bind to the CoV RNA genome and the nucleocapsid formation. In endoplasmic reticulum (ER)-Golgi, it helps in assembling and budding of SARS-CoV (de Haan and Rottier, 2005) . M Protein is an ample structural protein that maintains the shape of the viral envelope (Neuman et al. , 2011 , Tooze et al. , 1984 . E protein is the smallest of all the proteins available and is abundantly produced during viral infection and then incorporated in the viral envelope to mediate membrane fusion (Gallagher and Buchmeier, , directly to the angiotensin-converting enzyme 2 (ACE 2) at its peptidase domain (PD) site (Kumar et al. , 2018 , Li et al. , 2005 . Whereas the S2 subunit facilitates membrane fusion which is a paramount step for viral infection. S2 comprises a cleavage site for host proteases (Belouzard et al., 2009 , Millet and Whittaker, 2015 , Simmons et al. , 2005 . Based on data and analysis published by Statistical Research Department for Italy, there can be inferences that men may be more at risk than women (53.1% vs. 46.9% among total COVID-19 cases) (Floyd and Ferro, 2014) . Further, growing evidence shows that there is an increased mortality rate in male COVID-19 patients as compared to females underlying with chronic illness such as hypertension, which is the foremost reason for the comorbidity and mortality J o u r n a l P r e -p r o o f Journal Pre-proof , followed by diabetes mellitus, renal disorder, chronic obstructive pulmonary disease and cancer (Hussain et al. , 2020 , Sun et al. , 2020 , Valencia, 2020 . The infection and fatality rate is less in females, possibly due to strong immune response; less susceptibility to viral infections; high level of the protective hormone estrogen, progesterone and, presence of ACE 2 which is X- Chen et al. , 2020b , Conti and Younes, 2020 , Hanff et al. , 2020 , Kumar et al. , 2020 . However, in an article by World Economic Forum, it is suggested that COVID-19 fallout may be worse in women compared to men since i) women are on the front lines of the fight against , secondary villi. In the maternal stroma, ACE2 is expressed in the invading and intravascular trophoblast and decidual cells. ACE2 is also found in arterial and venous endothelium and smooth muscle of the umbilical cord (Pringle et al. , 2011 , Valdés et al. , 2006 . suppressed levels when compared with normal pregnancy subjects (Brosnihan et al. , 2004) . , pregnant women with COVID-19 admitted to Zhongnan Hospital of Wuhan University and all mothers underwent cesarean deliveries in their third trimester in negative pressure isolation rooms with all infection control measures. After delivery, all six infants were immediately isolated from the mother and show negative swab testing reports. However, out of six, two infants showed a high level of IgM antibodies with SARS-CoV-2 in the serum samples with no symptoms, later all infants were tested for viral RNA and showed negative reports (Zeng et al. , 2020a) . Nan Yu and colleagues in Wuhan, China reported the assessment of obstetric and neonatal outcomes of pregnancy with COVID-19 pneumonia in seven pregnant women. All patients were kept in isolation and on Antiviral treatment and oxygen therapy. The onset symptoms were identical to the non-pregnant individuals. All patients went under the caesarean section and three neonates were positive for SARS-CoV-2 (Yu et al. , 2020) . A report from Wuhan hospital mothers with COVID-19 gave birth to 33 neonates, out of whom, 3 neonates were infected with the SARS-CoV-2 and showed symptoms of pneumonia; from all 3 neonates, nasopharyngeal and anal swabs were taken and confirmed with COVID-19 on day 2 and 4, after birth. 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