Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Kalidhindi, Rama Satyanarayana Raju; Borkar, Niyati A.; Ambhore, Nilesh Sudhakar; Pabelick, Christina M.; Prakash, Y. S.; Sathish, Venkatachalem

doi:10.1152/ajplung.00391.2020

Cited by 56 publications

(77 citation statements)

References 40 publications

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“…Sex steroids -androgens and estrogens -influence the RAAS system [63,64] and sex-specific differences in ACE2 expression render males more vulnerable to renal and cardiovascular disease, with higher levels considered more detrimental [65][66][67]. Evidence suggests that sex steroids can influence ACE2 expression in the respiratory tract, and that higher ACE2 levels may be causally related to increased COVID-19 severity [67][68][69][70][71]. However, studies investigating ACE2 expression in respiratory tract tissues by sex have not consistently shown higher expression in males, highlighting that levels of ACE2 may not fully explain the observed male bias in severe COVID-19 disease [55,[71][72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex?

Shook

Bordt

Meinsohn

et al. 2021

Preprint

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Background: Sex differences in vulnerability to and severity of SARS-CoV-2 infection have been described in non-pregnant populations. ACE2 and TMPRSS2, host molecules required for viral entry, are regulated by sex steroids and expressed in the placenta. We sought to investigate whether placental ACE2 and TMPRSS2 expression vary by fetal sex and in the presence of maternal SARS-CoV-2 infection. Methods: Placental ACE2 and TMPRSS2 were quantified in 68 pregnant individuals (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. Maternal SARS-CoV-2 status was determined by nasopharyngeal RT-PCR. Placental SARS-CoV-2 viral load was quantified. RTqPCR was performed to quantify expression of ACE2 and TMPRSS2 relative to the reference gene YWHAZ. Western blots were performed on placental homogenates to quantify protein levels. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 and TMPRSS2 expression was analyzed by 2-way ANOVA. Results: SARS-CoV-2 virus was undetectable in all placentas. Maternal SARS-CoV-2 infection impacted TMPRSS2 placental gene and protein expression in a sexually dimorphic fashion (2-way ANOVA interaction p-value: 0.002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on placental ACE2 gene or protein expression. Placental TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman's rho=0.54, p=0.02) but not females (rho=0.23, p=0.34) exposed to maternal SARS-CoV-2. Conclusions: Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection. These findings may have implications for offspring vulnerability to placental infection and vertical transmission.These findings may have implications for offspring vulnerability to placental infection and vertical transmission.

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Section: Discussionmentioning

confidence: 99%

Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex?

Shook

Bordt

Meinsohn

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, ACE2 shows sexual dimorphic expression; male mice have increased renal and lung Ace2 protein expression compared with females [ 6 , 7 ]. Similarly, primary human airway cells from males have increased ACE2 protein expression compared with cells from females [ 8 ]. Additionally, TMPRSS2 protein expression is upregulated by androgens in androgen-sensitive human prostate adenocarcinoma cells [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19

Huffman

Rezq

Basnet

et al. 2021

IJMS

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SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

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“…In healthy subjects, serum ACE activity did not differ between sexes, but was lower in older men compared to younger men [39]. Recent studies in cultured human airway smooth muscle cells demonstrate higher ACE2 expression levels in males than females, suggesting a possible link between sex differences and outcomes with COVID-19 [40]. While we did not nd an association between plasma ACE (or ACE2) and mortality in COVID-19, the sample size was relatively small and analysis of larger cohorts is needed to address this possibility.…”

Section: Discussionmentioning

confidence: 94%

Sustained Dysregulation of the Plasma Renin-angiotensin System in Acute COVID-19

Burns

Cheng

Lee

et al. 2021

Preprint

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SARS-CoV-2 enters cells by binding to angiotensin-converting enzyme 2 (ACE2), and COVID-19 infection may therefore induce changes in the renin-angiotensin system (RAS). To determine the effects of COVID-19 on plasma RAS components, we measured plasma ACE, ACE2, and angiotensins I, (1-7), and II in 46 adults with COVID-19 at hospital admission and on days 2, 4, 7 and 14, compared to 50 blood donors (controls). We compared survivors vs. non-survivors, males vs. females, ventilated vs. not ventilated, and angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor-exposed vs. not exposed. At admission, COVID-19 patients had higher plasma levels of ACE (p=0.012), ACE2 (p=0.001) and angiotensin-(1-7) (p<0.001) than controls. Plasma ACE and ACE2 remained elevated for 14 days in COVID-19 patients, while plasma angiotensin-(1-7) decreased after 7 days. In adjusted analyses, plasma ACE was higher in males vs. females (p=0.042), and plasma angiotensin I was significantly lower in ventilated vs. non-ventilated patients (p=0.001). In summary, plasma ACE and ACE2 are increased for at least 14 days in patients with COVID-19 infection. Angiotensin-(1-7) levels are also elevated, but decline after 7 days. The results indicate dysregulation of the RAS with COVID-19, with increased circulating ACE2 throughout the course of infection.Clinical Trial Registration: https://clinicaltrials.gov/ Unique Identifier: NCT04510623

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Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

Cited by 56 publications

References 40 publications

Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex?

Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex?

SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19

Sustained Dysregulation of the Plasma Renin-angiotensin System in Acute COVID-19

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