Lead Author's Financial Disclosure: Nothing to disclose.
Study Funding: This study was conducted with financial support from Amarin Pharma Inc, Bridgewater, NJ.
Background/Synopsis: Angiotensin-converting enzyme (ACE) in the lungs catalyzes the formation of angiotensin II (Ang II) which has systemic pro-inflammatory and vasoconstrictive effects. The SARS-CoV-2 virus, responsible for COVID-19, has been shown to infect host cells via a homolog of ACE that leads to further complications in patients with underlying cardiovascular comorbidities, including dyslipidemia. The omega-3 fatty acid eicosapentaenoic acid (EPA) reduces inflammation and this may contribute to reduced cardiovascular events in patients with elevated triglycerides (REDUCE-IT). EPA is currently being tested in similar patients with cardiovascular disease or diabetes and at risk for COVID-19.
Objective/Purpose: This study tested the effects of EPA on protein expression in human pulmonary ECs under conditions of inflammation using the cytokine IL-6.
Methods: Human lung microvascular endothelial cells (HMVEC-L) were pretreated with vehicle or EPA (40 micromolar) in 2% FBS for 2 h, then challenged with IL-6 at 12 ng/ml for 24 h. Proteomic analysis was performed using LC/MS to capture relative expression levels of over 1,000 proteins. Only significant changes in protein expression between treatment groups >2-fold were analyzed. Expression levels of intercellular adhesion molecule-1 (ICAM-1) were measured by Western blot analysis. Specific pathway analysis was carried out using gene set enrichment analysis (GSEA).
Results: HMVEC-L pretreated with EPA and then challenged with IL-6 showed down-regulation of >60 proteins compared with untreated controls. Among the proteins significantly down-regulated by EPA was ACE by 3-fold (p<0.05) compared with IL-6 treated cells. The reduction in ACE expression with EPA correlated with reduced expression of other inflammatory proteins, including ICAM-1 (p<0.05). GSEA analysis also revealed changes in several pathways related to transcription regulation with EPA treatment.
Conclusions: These findings indicate that EPA reduced the expression of ACE following cytokine treatment, along with various inflammatory proteins. These studies support a novel effect of EPA on pulmonary ACE levels that may have therapeutic implications for patients at risk for cardiovascular disease as well as SARS-CoV-2.