Table 1.
Some genetic agents and uncontrolled immunothrombosis-induced interfering factors effective on miRNAs functions/expressions that could be beneficial for the treatment of critical COVID-19.
| Interfering factor | Effect | Ref | Expected results |
|---|---|---|---|
| miR-SNPs | |||
| rs2431697 T allele | Expression reduction of miR-146a | [183], [246] | Increased expression of Mac-1, TLR2, TLR4, IL-8, CD40L, and CXCL12, Upregulated activity of NADPH oxidases and excessive production of ROS, Enhanced activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| rs2910164 CC genotype | [243] | ||
| rs57095329 A/G genotype | [244] | ||
| rs767649 A/T allele | Expression elevation of miR-155 | [245], [247] | Excessive production of ROS, IL-8, and PAD4, Reduced expression of CFH, Activation, dysfunction, and pyroptosis of ECs, Increased activation of neutrophils and monocytes, Higher complement activation, Enhanced NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| rs353292 CT/TT variant | Expression reduction of miR-143 | [248] | Increased expression of TLR2 and PAI-1, Upregulated activation of neutrophils, monocytes, and PLTs, Reduced/inefficient fibrinolysis, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| rs74693964 C/T variant | Expression reduction of miR-145 | [249] | Higher expression of TF, FXI, HIF-2α, C3, and PAI-1, Elevated complement activation, Increased neutrophils persistence and monocytes activation, Reduced/inefficient fibrinolysis, Upregulated NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| Complement system components | |||
| Sublytic doses of MAC | Expression elevation of miR-328 and miR-616 | [214] | Increased expression/deposition of C3, Inhibition of CD46 and CD59, Higher complement activation, Enhanced NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| C5a | Expression reduction of miR-193 and miR-133a | [250] | Increased production of Fg and Mac-1, Reduced u-PA and fibrinolysis regulation, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| Excessive expression of miR-26b | Deviation from optimal expression level and inefficient function of this miRNA, based on the manifestations of the critical COVID-19, Reduced regulation of P-selectin, FVIII, and IFN-γ expressions, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
||
| C3 | Expression reduction of miR-145 | [216] | Higher expression of TF, FXI, HIF-2α, C3, and PAI-1, Enhanced complement activation, Increased neutrophils persistence and monocytes activation, Reduced/inefficient fibrinolysis, Elevated NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| NADPH oxidases and ROS | |||
| ------- | Expression reduction of miR-29a/b, miR-29c-3p, miR-24–2, miR-145, miR-128, miR-let-7, miR-199a, miR-125b, and miR-126a | [192], [251], [252], [257], [258] | Increased expression/production of NADPH oxidases, ROS, Fg, VWF, TF, FIX, FX, FXI, HIF-1/2α, CXCL12, C3, PAI-1, IL-6, TLR4, TLR7, αIIbβ3, SNAP23, and P2Y12, Elevated neutrophils persistence and monocytes activation, Higher complement activation, Inefficient fibrinolysis, PLTs activation and degranulation, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| ------- | Expression elevation of miR-21, miR-146a, miR-9, and miR-143 | [251], [253], [254], [255], [256], [259] | Deviation from optimal expression levels and inefficient functions of these miRNAs, based on the manifestations of the critical COVID-19, Reduced regulation of Mac-1, TLR2, TLR4, IL-8, CD40L, CXCL12, and PAI-1 expressions, Upregulated activity of NADPH oxidases and excessive production of ROS, Decreased expression of CFH, Elevated activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Higher complement activation, Reduced/inefficient fibrinolysis, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| PAD enzymes and histone citrullination | |||
| ------- | Reduced expression of miR-let-7c-2, miR-29c, and miR-16 | [260], [261] | Upregulated expression of IL-6, TLR4, TLR7, SNAP23, and Fg, Enhanced activity of NADPH oxidases and excessive production of ROS, PLTs activation and degranulation, Activation, dysfunction, and pyroptosis of ECs, Increased neutrophils and monocytes activation, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| Hypoxia/hypoxemia | |||
| ------- | Expression elevation of miR-155, miR-21, miR-103, and miR-146a | [262], [264], [265], [266] | Deviation from optimal expression levels and inefficient functions of these miRNAs, based on the manifestations of the critical COVID-19, Upregulated activity of NADPH oxidases and excessive production of ROS, IL-8, and PAD4, Reduced expression of CFH, Decreased regulation of VWF, TF, CXCL12, Mac-1, TLR2, TLR4, IL-8, and CD40L expressions, Higher complement activation, Enhanced activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| ------- | Expression reduction of miR-150, miR-25, miR-15a, miR-205, and miR-34a | [267], [268], [269], [270], [271] | Elevated activity of NADPH oxidases and excessive production of ROS, αIIbβ3, IL-6R, and FVIII, Enhanced activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Higher complement activation, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| CXCL12 | Inefficient function of miR-31 | [237] | Increased expression of αIIbβ3 and CXCL12, Enhanced activation of neutrophils, monocytes, and PLTs, Upregulated NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| Coagulation and fibrinolysis mediators | |||
| Fibrin | Expression reduction of miR-146a | [272] | Increased expression of Mac-1, TLR2, TLR4, IL-8, CD40L, and CXCL12, Upregulated activity of NADPH oxidases and excessive production of ROS, Enhanced activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| PDGF-BB | Expression reduction of miR-145 | [273] | Higher expression of TF, FXI, HIF-2α, C3, and PAI-1, Elevated complement activation, Increased neutrophils persistence and monocytes activation, Reduced/inefficient fibrinolysis, Upregulated NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| aPC | Expression reduction of miR-199a, miR-29b, and miR-211 | [275] | Elevated expression of HIF-1α, Fg, and HIF-1α-induced CXCL12 Increased neutrophils persistence, Upregulated complement activation, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| t-PA | Expression reduction of miR-15a | [276] | Elevated expression of αIIbβ3, Enhanced activation of neutrophils, monocytes, and PLTs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
| Inefficient function of miR-146a | [272] | Increased expression of Mac-1, TLR2, TLR4, IL-8, CD40L, and CXCL12, Upregulated activity of NADPH oxidases and excessive production of ROS, Enhanced activation of neutrophils, monocytes, and PLTs, Activation, dysfunction, and pyroptosis of ECs, Increased NETosis, Severe inflammation and coagulation, Uncontrolled immunothrombosis |
|
Abbreviations: αIIbβ3, Integrin αIIbβ3; aPC, Activated protein C; C, Complement component; CD40L, Cluster of differentiation 40 ligand; CFH, Complement factor H; CXCL12, C-X-C motif chemokine ligand 12; ECs, Endothelial cells; Fg, Fibrinogen; FVIII, Factor VIII; FIX, Factor IX; FX, Factor X; FXI, Factor XI; HIF, Hypoxia-inducible factor; IFN-γ, Interferon gamma; IL, Interleukin; IL-6R, IL-6 receptor; Mac-1, Macrophage-1 antigen; MAC, Membrane attack complex; miRNAs, MicroRNAs; miR-SNPs, MicroRNA-single nucleotide polymorphisms; NADPH oxidase, Nicotinamide adenine dinucleotide phosphate oxidase; NET, Neutrophil extracellular trap; PAD, Protein arginine deiminase; PAI-1, Plasminogen Activator Inhibitor-1; PDGF-BB, Platelet-derived growth factor-BB; PLTs, Platelets; ROS, Reactive oxygen species; SNAP23, Synaptosomal-associated protein 23; TF, Tissue factor; TLR, Toll-like receptor; t-PA, Tissue plasminogen activator; u-PA, Urokinase plasminogen activator; VWF, Von Willebrand factor.