Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can infect several organs, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 is myocardial injury, which is associated with a high risk of mortality. Myocardial injury, caused directly or indirectly by SARS-CoV-2 infection, can be triggered by inflammatory processes that lead to damage to the heart tissue. Since one of the hallmarks of severe COVID-19 is the “cytokine storm”, strategies to control inflammation caused by SARS-CoV-2 infection have been considered. Cannabinoids are known to have anti-inflammatory properties by negatively modulating the release of pro-inflammatory cytokines. Herein, we investigated the effects of the cannabinoid agonist WIN 55,212-2 (WIN) in human iPSC-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. WIN did not modify angiotensin-converting enzyme II protein levels, nor reduced viral infection and replication in hiPSC-CMs. On the other hand, WIN reduced the levels of interleukins six, eight, 18 and tumor necrosis factor-alpha (TNF-α) released by infected cells, and attenuated cytotoxic damage measured by the release of lactate dehydrogenase (LDH). Our findings suggest that cannabinoids should be further explored as a complementary therapeutic tool for reducing inflammation in COVID-19 patients.
Highlights
We aimed to investigate the effects of a synthetic cannabinoid, that acts as a mixed cannabinoid receptors type 1 (CB1)/CB2 receptors agonist, in hiPSC-CMs infected by SARS-CoV-2
Human cardiomyocytes express cannabinoid receptor 1 but WIN does not modulate ACE2 expression As a first step to investigate the influence of cannabinoid receptors in SARS-CoV-2 infection of human cardiomyocytes, we checked whether hiPSC-CMs expressed CB1 and CB2 receptors
We found that hiPSC-CMs express only CB1 receptor mRNA (Fig. S1A), which was confirmed by CB1 protein expression (Fig. S1B)
Summary
A post-mortem study of a child with COVID-19 revealed diffuse myocardial interstitial inflammation with immune cells infiltration and necrosis (Dolhnikoff, 2020). High expression of Angiotensin-Converting Enzyme II (ACE2) in the heart has been correlated with severe COVID-19 and susceptibility of patients with pre-existing cardiac conditions (Chen et al, 2020a; Thum, 2020; Sharma et al, 2020; Dariolli et al, 2021). In vitro studies have shown that SARS-CoV-2 infects iPSC-derived cardiomyocytes (hiPSC-CMs) through ACE2 (Sharma et al, 2020; Dariolli et al, 2021), leading to upregulation of inflammation-related genes, including IL-6, IL-8, and TNF-a (Wong et al, 2020; Kwon et al, 2020). The correlation between inflammation and heart damage in post-mortem and in vitro studies points to the need for finding strategies that mitigate direct SARS-CoV-2 cardiac outcomes
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