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An angiotensin receptor blocker in the presence of sars cov2 pseudovirus does not change protein expression of ace2 in human heart cell models
Circulation ; 144(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1631511
ABSTRACT

Introduction:

ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in COVID-19 raised concern due to reported increases in ACE2, the cell receptor for SARS-CoV2. We tested the hypothesis that ARB (Losartan) and ACEI (Captopril) do not impact SARS-CoV2 associated ACE2 expression in cardiomyocytes (CMs).

Methods:

Beating monolayer ventricular CMs were generated from human iPSCs and grown as engineered heart tissue constructs (EHTs), which mimic a more mature phenotype than monolayer CMs. Drug treatments (24hrs) without pseudovirus were applied to EHTs (A) Vehicle, 1μM Losartan (ARB), 1μM Angiotensin II (AngII), 1μM Losartan+1μM Ang II;(B) Vehicle, 1μM Captopril, 1μM Ang I, or 1μM AngI+1μM Captopril with 2-3 replicates for each combination and RNAseq as outcome. Drug treatment A only was repeated in monolayer CMs with a 5-6 day to rVSV-SARS-Cov2SpikeLuciferase-FLAG tagged pseudovirus (2-4 replicates) with immunoblotting for ACE2, Cathepsin B (CTSB) and Furin proteins.

Results:

Immunoblot densitometry showed abundant ACE2 protein in untreated CMs and EHTs. A focused mRNA analysis of 12 genes associated with SARS-Cov2 entry and processing (EHTs) revealed no significant changes in expression of ACE2, NRP1, CTSB, CTSL and FURIN due to Losartan or Captopril treatment. There was a nonsignificant trend towards Losartan-induced increase in AGTR1 with attenuation when AngII was administered, while ITGA5 trended upwards with Losartan+AngII. AGTRI also trended upwards with Captopril and AngI+Captopril. Upon pseudoviral challenge, CMs demonstrated increased ACE2 (55%) and slightly decreased Furin (24%) protein, with unchanged CTSB, although results were not statistically significant. Losartan addition, regardless of AngII, did not alter SARS-CoV2Spike pseudovirus mediated changes of ACE2, Furin or CTSB proteins.

Conclusions:

Losartan or Captopril did not substantially alter gene expression of ACE2, CTSB, CTSL, FURIN and NRP1 in EHTs without pseudovirus. Losartan did not show convincing evidence for pseudoviral mediated changes of proteins important for viral entry and processing in CM cell models.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Circulation Year: 2021 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Circulation Year: 2021 Document Type: Article