APA
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Lei, Y., Zhang, J., Schiavon, C. R., He, M., Chen, L., Shen, H., … Shyy, J. (2021). SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circulation Research.
Chicago/Turabian
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Lei, Yuyang, Jiao Zhang, Cara R. Schiavon, M. He, Lili Chen, Hui Shen, Yichi Zhang, et al. “SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2.” Circulation Research (2021).
MLA
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Lei, Yuyang, et al. “SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2.” Circulation Research, 2021.
BibTeX Click to copy
@article{yuyang2021a,
title = {SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2},
year = {2021},
journal = {Circulation Research},
author = {Lei, Yuyang and Zhang, Jiao and Schiavon, Cara R. and He, M. and Chen, Lili and Shen, Hui and Zhang, Yichi and Yin, Qian and Cho, Yoshitake and Andrade, Leonardo R. and Shadel, G. S. and Hepokoski, M. and Lei, Ting and Wang, Hongliang and Zhang, Jin and Yuan, J. and Malhotra, A. and Manor, U. and Wang, Shengpeng and Yuan, Z. and Shyy, J.}
}
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection relies on the binding of S protein (Spike glycoprotein) to ACE (angiotensinconverting enzyme) 2 in the host cells. Vascular endothelium can be infected by SARS-CoV-2,1 which triggers mitochondrial reactive oxygen species production and glycolytic shift.2 Paradoxically, ACE2 is protective in the cardiovascular system, and SARS-CoV-1 S protein promotes lung injury by decreasing the level of ACE2 in the infected lungs.3 In the current study, we show that S protein alone can damage vascular endothelial cells (ECs) by downregulating ACE2 and consequently inhibiting mitochondrial function. We administered a pseudovirus expressing S protein (Pseu-Spike) to Syrian hamsters intratracheally. Lung damage was apparent in animals receiving PseuSpike, revealed by thickening of the alveolar septa and increased infiltration of mononuclear cells (Figure [A]). AMPK (AMP-activated protein kinase) phosphorylates ACE2 Ser-680, MDM2 (murine double minute 2) ubiquitinates ACE2 Lys-788, and crosstalk between AMPK and MDM2 determines the ACE2 level.4 In the damaged lungs, levels of pAMPK (phospho-AMPK), pACE2 (phospho-ACE2), and ACE2 decreased but those of MDM2 increased (Figure [B], i). Furthermore, complementary increased and decreased phosphorylation of eNOS (endothelial NO synthase) Thr-494 and Ser-1176 indicated impaired eNOS activity. These changes of pACE2, ACE2, MDM2 expression, and AMPK activity in endothelium were recapitulated by in vitro experiments using pulmonary arterial ECs infected with Pseu-Spike which was rescued by treatment with N-acetyl-L-cysteine, a reactive oxygen species inhibitor (Figure [B], ii). We next studied the impact of S protein on mitochondrial function. Confocal images of ECs treated with S1 protein revealed increased mitochondrial fragmentation, indicating altered mitochondrial dynamics (Figure [C], i). To examine whether these mitochondrial changes were due, in part, to the decreased amount of ACE2, we overexpressed ACE2 S680D (ACE2-D, a phospho-mimetic ACE2 with increased stability) or S680L (ACE2-L, a dephospho-mimetic with decreased stability)4 in ECs. As shown in Figure [C], ii, ECs with ACE2-L had a higher number of fragmented mitochondria when compared to those with ACE2-D. Performing oxygen consumption rate and extracellular acidification rate assays, we found that ECs overexpressing ACE2-L had reduced basal mitochondrial respiration, ATP production, and maximal respiration compared to ECs overexpressing ACE2-D (Figure [D], i). Moreover, ACE2-L overexpression caused increased basal acidification rate, glucose-induced glycolysis, maximal glycolytic capacity, and glycolytic reserve (Figure [D], ii). Also, ECs incubated with S1 protein had attenuated mitochondrial function but increased
