Microparticles and endothelial function in patients with COVID-19: effects of bradykinin blockade

Abstract

Cardiovascular complications are a common feature affecting patients (40-80%) recovering from SARS-CoV-2 infection. Cardiovascular symptoms can persist for until 12 months after COVID-19 diagnosis. Therefore, it is important to elucidate the pathophysiological mechanisms underlying cardiovascular complications in the post-COVID-19 syndrome and improve therapeutic intervention. Microparticles (MP) are biomarkers of cell injury with biological activity. MP are known to mediate endothelial damage. Endothelial dysfunction is a possible mechanism involved in cardiovascular complications associated with post-COVID-19 syndrome. Increased circulating levels of MP correlated with COVID-19 severity and can persist elevated for months. Therefore, circulating MP could impact endothelial function in the setting of long COVID-19. Two pharmacological inhibitors of the kinin-kallikrein system (KKS) that are currently approved for the treatment of hereditary angioedema, B2 receptor antagonist icatibant (Firazyr), and inhibitor of C1 esterase/kallikrein (Berinert) resulted in significant improvement of lung computed tomography scores and increased blood eosinophils. Therefore, pharmacological inhibition of the KKS was safe and improved COVID-19 recovery. Angiontensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is coexpressed with elements of the KKS and renin-angiotensin system in alveolar cells. Therefore, bradykinin may be an important extension of ACE2-SARS-CoV-2 activation, and then contributing to cardiovascular damage associated to COVID-19 such as endothelial dysfunction. In the present study, we propose to investigate number and endothelial effects of circulating MP isolated from plasma samples of 1 and 6 months post-COVID-19 patients that were treated or not with B2R antagonist Firazyr or C1 inhibitor Berinert during acute phase of infection. We hypothesized that pharmacological inhibition of the KKS result in improved MP levels and bioactivity in long COVID-19. For this, MP will be quantified and isolated from plasma samples collected 1- and 6-months following discharge of patients hospitalized with severe COVID-19 included in the ITHACA trial (COVID-19 Treated by c1 esterase inHibitor And iCAtibant) (PMID 33472675). In isolated MP and endothelial cells exposed in vitro to MP, we will investigate the gene and protein expression of proinflammatory factors, anti-and pro-oxidant factors, and renin-angiotensin components. In addition, the effect of MP on the endothelium-dependent vasodilation will be tested in health arteries in situ. (AU)