Inflammatory Mechanisms in COVID-19 and Atherosclerosis: Current Pharmaceutical Perspectives

Abstract

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with excess mortality worldwide. The cardiovascular system is the second most common target of SARS-CoV-2, which leads to severe complications, including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism, as well as other major thrombotic events because of direct endothelial injury and an excessive systemic inflammatory response. This review focuses on the similarities and the differences of inflammatory pathways involved in COVID-19 and atherosclerosis. Anti-inflammatory agents and immunomodulators have recently been assessed, which may constitute rational treatments for the reduction of cardiovascular events in both COVID-19 and atherosclerotic heart disease.

Keywords: COVID-19; SARS-CoV-2; anti-inflammatory treatment; atherosclerosis; inflammation.

Figure 1

(i) Atherosclerosis: Involves the activation of the endothelium, which upregulates inflammatory signaling mechanisms via the release of inflammatory cytokines and chemokines. LDL particles accumulate in the tunica intima and are subjected to oxidative modification. Circulating monocytes bind to adhesion molecules expressed on the activated endothelial cell surface and migrate to the intimal layer. Subsequently, they transform to macrophages and express receptors that bind to oxidized LDL particles, ultimately turning into foam cells. T lymphocytes as well as vascular smooth muscle cells situated in the medial layer, also migrate to the intimal layer. (ii) COVID-19: “The role of endothelial cells in SARS-CoV-2 infection”. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds with Angiotensin-converting enzyme 2 (ACE2) on the cell membrane of the host cells. Cell invasion also depends on the presence of the protease Transmembrane protease serine 2 (TMPRSS-2) that can cleave the viral spike. The recombinant protein of human ACE2 fused with the Fc region of the human immunoglobulin IgG1 (rACE2-IgG1) binds with high affinity to the receptor-binding domain of SARS-CoV-2. In patients diagnosed with severe COVID-19, increased levels of pro-inflammatory cytokines, particularly the soluble interleukin 2-receptor (IL-2R) and interleukin-6 (IL-6), have been observed. Endothelial cells (ECs) express both the IL-6 receptor (IL-6R) and IL-2R on their surface. Soluble IL-2R (sIL-2R) is mostly secreted by activated T helper lymphocytes but might also be secreted by ECs. The binding of IL-6 and IL-2 on their receptors induces a capillary leak. Moreover, IL-6 signaling induces the secretion by ECs of more IL-6 and other cytokines. The continuous burdening of the endothelium leads to further secretion of inflammatory cytokines and the over-reaction of the immune system, the so-called “Cytokine Storm”. ΡAΙ-1 = Plasminogen activator inhibitor-1, TNF = Tumor Necrosis Factor, ICAM = Intercellular Adhesion Molecule 1, VCAM = Vascular cell adhesion protein 1, PECAM = Platelet endothelial cell adhesion molecule-1, MCP-1 = monocyte chemoattractant protein-1, G-CSF = Granulocyte colony-stimulating factor, IP-10 = Interferon gamma-induced protein 10, MIP-1 = Macrophage inflammatory protein-1, IFN = Interferon.