ACE2 mouse models: a toolbox for cardiovascular and pulmonary research

Figures

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  Fig. 1. Mechanisms of ACE2 post-translational regulation and viral infection. Angiotensin (Ang)-II binding to its type 1 receptor (AT1R) leads to internalization of the AT1R–ACE2 complex to early endosomes, thus preventing further Ang-II hydrolysis into Ang-(1–7). AT1R is then recycled to the plasma membrane, while ACE2 is degraded in lysosomes (left). In addition, AT1R activation by Ang-II leads to the recruitment of ADAM17 from cytoplasmic pools and translocation to the plasma membrane, where it sheds the ACE2 ectodomain to release a secreted form of the enzyme (sACE2) (middle). Finally, ACE2 serves as the receptor for SARS-CoV-2, triggering endocytosis via clathrin-coated pits. Spike protein priming by serine protease TMPRSS2 is also required for viral entry (right).

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  Fig. 2. Targeting strategies of the mAce2 gene in KO and conditional KO mice. Schematic of the different ACE2 KO models. The mouse Ace2 gene contains 19 exons, and the regions deleted in these models are highlighted in purple. Exon 9 (green) codes for the ACE2 active site. The floxed exon is flanked by the LoxP sites.

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  Fig. 3. Expression of ACE2 in transgenic and KI mice. Schematic of the different gain-of-function models driven by specific mouse (gold), human (green), or other (blue) promoters for ubiquitous or targeted ACE2 overexpression. ROSA26: locus used for constitutive and ubiquitous gene expression; K18: cytokeratin 18 promoter targeting epithelial cells; CMV: cytomegalovirus promoter for constitutive expression; HFH4: lung ciliated epithelial cell-specific promoter; Syn: synapsin1 promoter for neuronal expression; α-MHC: α-myosin heavy chain for cardiac-specific expression. LoxP: sites for cre-recombinase-mediated excision of the stop codon.