tetano
Editor, Senior Moderator
J Transl Med
. 2023 Feb 9;21(1):103.
doi: 10.1186/s12967-023-03945-7.
ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway
Feng Chen[SUP] #[/SUP][SUP] 1 2 [/SUP], Yanting Chen[SUP] #[/SUP][SUP] 1 3 [/SUP], Qiongwei Ke[SUP] #[/SUP][SUP] 1 [/SUP], Yongxiang Wang[SUP] 1 [/SUP], Zheng Gong[SUP] 4 [/SUP], Xiongjin Chen[SUP] 1 [/SUP], Yujie Cai[SUP] 1 [/SUP], Shengnan Li[SUP] 1 [/SUP], Yuanhong Sun[SUP] 5 [/SUP], Xiaoping Peng[SUP] 1 [/SUP], Yao Ji[SUP] 1 [/SUP], Tianzhen Zhang[SUP] 1 [/SUP], Wenxian Wu[SUP] 6 7 8 [/SUP], Lili Cui[SUP] 9 [/SUP], Yan Wang[SUP] 10 [/SUP]
Affiliations
Abstract
Background: Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes.
Methods: A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression.
Results: ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7.
Conclusions: ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.
Keywords: ACE2; ApoE4; COVID-19; SARS-CoV-2; Spike.
. 2023 Feb 9;21(1):103.
doi: 10.1186/s12967-023-03945-7.
ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway
Feng Chen[SUP] #[/SUP][SUP] 1 2 [/SUP], Yanting Chen[SUP] #[/SUP][SUP] 1 3 [/SUP], Qiongwei Ke[SUP] #[/SUP][SUP] 1 [/SUP], Yongxiang Wang[SUP] 1 [/SUP], Zheng Gong[SUP] 4 [/SUP], Xiongjin Chen[SUP] 1 [/SUP], Yujie Cai[SUP] 1 [/SUP], Shengnan Li[SUP] 1 [/SUP], Yuanhong Sun[SUP] 5 [/SUP], Xiaoping Peng[SUP] 1 [/SUP], Yao Ji[SUP] 1 [/SUP], Tianzhen Zhang[SUP] 1 [/SUP], Wenxian Wu[SUP] 6 7 8 [/SUP], Lili Cui[SUP] 9 [/SUP], Yan Wang[SUP] 10 [/SUP]
Affiliations
- PMID: 36759834
- DOI: 10.1186/s12967-023-03945-7
Abstract
Background: Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes.
Methods: A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression.
Results: ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7.
Conclusions: ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.
Keywords: ACE2; ApoE4; COVID-19; SARS-CoV-2; Spike.