Figure 1. Suggested pathways for SARS-CoV-2 mediated ACE
upregulation and ACE 2 downregulation. Endothelial activation pathways
leading to intense pulmonary vasoconstriction in COVID-19: SARS-CoV-2
spike protein binds to ACE 2 on the pulmonary epithelium and causes
TACE-mediated shedding of ACE 2 ectodomain resulting in downregulation
of ACE 2. Activated TACE causes concomitant shedding of soluble TNF α
and IL-6 receptor on the apical, basal and basolateral side of the
epithelial cell. TNF α causes increased expression of AT1R on
endothelial cells. This results in increased AT II mediated harmful
effects and reduced AT 1-7 mediated protective actions. High AT II
activity reduces the expression of AMPK, a mediator for balance between
ACE and ACE 2. AT II increase the conversion of TACE dimer to TACE
monomer (active form) via AT1R/p38 MAPK and AT1R/ERK pathway. Thus, a
vicious cycle of ACE/ACE 2 overactivity is established (Mechanistic
pathways as shown in Inset). Due to relatively high expression of AT1R
on pulmonary endothelium, vasoconstrictive actions of AT1R are only
partly counterbalanced by AT2R mediated vasorelaxation. Increased levels
ET-1 and peroxynitrite with relatively reduced levels of NO results in
intense pulmonary vasoconstriction. (Pathways highlighted green are
relatively activated while red highlights represent relative
inactivation)
ACE: angiotensin-converting enzyme; ACE 2: angiotensin-converting enzyme
2; AT II: Angiotensin II; AT I: Angiotensin I; AT1R: Ang II type-1
receptor; AT2R: Ang II type-2 receptor; NOX: nicotinamide adenine
dinucleotide phosphate oxidase; LOX-1: Lecithin-Like oxLDL Receptor-1;
ETAR: Endothelin-1A receptor; B2R: B2 receptor; eNOS: endothelial nitric
oxide synthase; SOD: superoxide dismutase; NO: nitric oxide; PLC:
phospholipase C; PKC: protein kinase C; TACE: Tumor necrosis factor
alpha converting enzyme; s-TNF-α: soluble tumor necrosis factor alpha;
IL6R1: interleukin 6 receptor; IL6: interleukin 6; AT 1-7:angiotensin
1-7; PI3K/PKB/Akt: phosphoinositide-3-kinase–protein kinase B/Akt;
AMPK: 5’ adenosine monophosphate-activated protein kinase; miR:
microRNA; EC: endothelial cell; VSMC: vascular smooth muscle cell.