ACE2 was observed as the cell surface receptor of the SARS-CoV-2 virus. Interestingly, we also found ACE2 positivity inside the cell nucleus. The ACE2 levels changed during cell differentiation and aging and varied in distinct cell types. We observed ACE2 depletion in the aortas of aging female mice, similarly, the aging caused ACE2 decrease in the kidneys. Compared with that in the heart, brain and kidneys, the ACE2 level was the lowest in the mouse lungs. In mice exposed to nicotine, ACE2 was not changed in olfactory bulbs but in the lungs, ACE2 was upregulated in females and downregulated in males. These observations indicate the distinct gender-dependent properties of ACE2. Differentiation into enterocytes, and cardiomyocytes, caused ACE2 depletion. The cardiomyogenesis was accompanied by renin upregulation, delayed in HDAC1-depleted cells. In contrast, vitamin D2 decreased the renin level while ACE2 was upregulated. Together, the ACE2 level is high in non-differentiated cells. This protein is more abundant in the tissues of mouse embryos and young mice in comparison with older animals. Mostly, downregulation of ACE2 is accompanied by renin upregulation. Thus, the pathophysiology of COVID-19 disease should be further studied not only by considering the ACE2 level but also the whole renin-angiotensin system.

• Keywords
• ACE2, embryonic heart, human kidney embryonic cells, lung cancer cells, renin,
• MeSH
• Angiotensin-Converting Enzyme 2 metabolism   MeSH
• Cell Differentiation physiology   MeSH
• A549 Cells MeSH
• HT29 Cells MeSH
• COVID-19 epidemiology   pathology   virology   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Mice MeSH
• Pandemics MeSH
• Gene Expression Regulation physiology   MeSH
• Renin-Angiotensin System physiology   MeSH
• Renin metabolism   MeSH
• SARS-CoV-2 pathogenicity   MeSH
• Sex Factors MeSH
• Aging physiology   MeSH
• Age Factors MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Angiotensin-Converting Enzyme 2 MeSH
• Renin MeSH

It has become evident that epitranscriptome events, mediated by specific enzymes, regulate gene expression and, subsequently, cell differentiation processes. We show that methyltransferase-like proteins METTL3/METTL14 and N6-adenosine methylation (m6A) in RNAs are homogeneously distributed in embryonic hearts, and histone deacetylase (HDAC) inhibitors valproic acid and Trichostatin A (TSA) up-regulate METTL3/METTL14 proteins. The levels of METTL3 in mouse adult hearts, isolated from male and female animals, were lower in the aorta and pulmonary trunks when compared with atria, but METT14 was up-regulated in the aorta and pulmonary trunk, in comparison with ventriculi. Aging caused METTL3 down-regulation in aorta and atria in male animals. Western blot analysis in differentiated mouse embryonic stem cells (mESCs), containing 10-30 percent of cardiomyocytes, showed METTL3/METTL14 down-regulation, while the differentiation-induced increased level of METTL16 was observed in both wild type (wt) and HDAC1 depleted (dn) cells. In parallel, experimental differentiation in especially HDAC1 wild type cells was accompanied by depletion of m6A in RNA. Immunofluorescence analysis of individual cells revealed the highest density of METTL3/METTL14 in α-actinin positive cardiomyocytes when compared with the other cells in the culture undergoing differentiation. In both wt and HDAC1 dn cells, the amount of METTL16 was also up-regulated in cardiomyocytes when compared to co-cultivated cells. Together, we showed that distinct anatomical regions of the mouse adult hearts are characterized by different levels of METTL3 and METTL14 proteins, which are changed during aging. Experimental cell differentiation was also accompanied by changes in METTL-like proteins and m6A in RNA; in particular, levels and distribution patterns of METTL3/METTL14 proteins were different from the same parameters studied in the case of the METTL16 protein.

• Keywords
• METTL-like enzymes, RNA methylation, cardiomyogenesis, epigenetics, epitranscriptomics,
• MeSH
• Adenosine analogs & derivatives   genetics   metabolism   MeSH
• Cell Differentiation MeSH
• HEK293 Cells MeSH
• HeLa Cells MeSH
• Myocytes, Cardiac cytology   metabolism   MeSH
• Humans MeSH
• Methyltransferases metabolism   MeSH
• Mouse Embryonic Stem Cells cytology   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Aging metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine MeSH
• Methyltransferases MeSH
• METTL14 protein, human MeSH Browser
• Mettl14 protein, mouse MeSH Browser
• METTL16 protein, human MeSH Browser
• Mettl3 protein, mouse MeSH Browser