Other chemical exposures besides drugs such as ACE inhibitors (ACE-Is) and angiotensin II receptor blocker (ARBs) can influence the expression of ACE2.  The following have been shown to increase ACE2 expression levels:

- increased dietary potassium
- intermittent fasting
- nicotine
- Vitamin D
- compounds that interact with SIRT1

Non-Drug Exposures that Increase ACE2 Expression

Sirtuin 1 (SIRT1) is a gene that is expressed next to the promoter region of the ACE2 gene.  Increased expression or activation of SIRT1 is positively associated with ACE2 expression.  Factors that increase SIRT1 expression or activation include:

- calorie restriction
- resveratrol
- Vitamin C
- aspirin
- metformin
- vitamin B3

This may explain why a large Vitamin C dose can possibly have a rescuing effect for COVID-19 patients with severe acute respiratory distress syndrome.

SIRT1 Modulates ACE2 Expression

- Cardiovascular disease (CVD)
- Use of anti-hypertension medications

Factors that can potentially increase ACE2 expression in the Cardiovascular System 

miRNAs that are homologous to the 3' end of the ACE2 gene were assessed using the data set from the Wang research group to determine if ACE2 expression was modulated by smoking.  miR-1246 is complementary to the  3′ untranslated region (3′UTR) of ACE2 mRNA.  Predicted base pairing was assessed using TargetScanHuman 7.2 (http://www.targetscan.org/vert_72/).  Affymetirx miRNA 2.0 arrays and TaqMan PCR reveal that miR-1246 expression is significantly decreased in smokers compared to nonsmokers (**P < 0.01 and ***P < 0.001).  This miRNA may be involved in the mechanism that regulates ACE2 expression in the SAE. 

miR-1246 Levels May Modulate ACE2 Expression Levels in the Small Airway Epithelium

- drug mediators
- non-drug mediators
- genetic mediators
- disease states

Michigan State University

- subcellular expression
- tissue and organ expression
- mediators that influence expression
- comparing to TMPRSS2 expression
- circulating expression
- expression in embryonic development

ACE2 Expression

Data from primary manuscripts and microscopy screenings were used to assign a confidence level to the likelihood of different subcellular locations expressing ACE2.  This study showed that the extracellular space and plasma membrane are the most likely places to express ACE2 (confidence = 5), and the Golgi apparatus is the least likely (confidence = 1) out of these listed locations.  

Subcellular Expression of ACE2

Mediators that Infleunce ACE2 Expression

- Increased Concentrations of Circulating ACE2 is Associated with Mild COVID-19 Symptoms 
- Circulating ACE2 expression compared to circulating ACE

Expression of Circulating ACE2 and COVID-19

Pregnant mice were used to assess the expression levels of the following genes associated with SARS-CoV-2, inflammation, and other viral diseases:

- ACE2: cellular receptor for the SARS-CoV-2 virus
- TMPRSS2: serine protease involved in cellular entry of the SARS-CoV-2 virus
- St3gal4: related to the influenza virus
- St6gal1: related to the influenza virus
- Ifngr1: related to inflammation
- Tnfrsf1a: related to inflammation

Mice were sacrificed at the following timepoints:

- E12.5: embryonic day 12 (gravid females are sacrificed)
- E14.5: embryonic day 14 (gravid females are sacrificed)
- P1: day pups are born (pups are sacrificed)

Epithelium (Epi) and mesenchyme (Mes) tissue were collected from the soft pallets (SP) and tongues (T) of the different developmental stages.  Notably, ACE2 expression was only observed in large quantities in P1 mice, and TMPRSS2 expression increased throughout the developmental process.  FPKM: fragments per kilobase million reads

ACE2 and Other SARS-CoV-2 Related Gene Expression in Mouse Development

ACE2 is expressed throughout many human tissues and organs. This node organizes the tissue- and organ-level expression findings for ACE2, covering: expression in cancer tissue; expression in the human airway epithelium; expression in the human brain; ACE2 protein and mRNA expression levels across tissues; and the relationship between tissue ACE2 expression and COVID-19.

ACE2 Expression in Tissue and Organs

Comparing the expression of TMPRSS2 and ACE2 reveals their overlaps and differences across human tissues and demographics. Both genes are coexpressed in respiratory and intestinal cells, and their overall expression levels are largely similar across sexes. However, their primary expression sites differ significantly: TMPRSS2 is expressed most highly in the prostate and more than ACE2 in the lungs, whereas ACE2 is most highly expressed in the testes.

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