Table 1.
Therapeutic approaches against atherosclerosis.
| Intervention type | Experimental or clinical condition | Subject | Antiatherogenic effects |
|---|---|---|---|
| Clinical studies in humans | |||
| Clopidogrel | Randomized, placebo-controlled study involving patients with coronary artery disease and chronic aspirin therapy (n = 113) [204] | Human | P2Y12 receptor antagonist ↓ CD40L and RANTES plasma levels |
| Atorvastatin | Internal mammary artery from patients scheduled for coronary artery bypass graft surgery (n = 492) [211] | Human | Improved vascular NO bioavailability ↓ the production of vascular O2− |
| Evolocumab | Prospective, nonrandomized study in patients with heterozygous familial hypercholesterolemia (n = 11) [235] | Human | Inhibited PCSK9 receptor ↓ LDL and apolipoprotein B levels |
| Anakinra | Double-blind randomized study in patients with rheumatoid arthritis (n = 23) [260] | Human | IL-1 receptor antagonist Improved vascular function ↓ IL-6 and ET-1 |
| Canakinumab | Double-blind, multinational phase IIb trial in patients with well-controlled diabetes mellitus (n = 556) [146] | Human | Inhibited IL-1β ↓ CRP, IL-6, and fibrinogen levels |
| Tocilizumab | Double-blind, placebo-controlled trial in patients with non-ST elevation myocardial infarction (n = 117) [267] | Human | Inhibited IL-6 Prevented the increase of serum PCSK9 levels |
| Colchicine | Double-blind, randomized, placebo-controlled study in patients with coronary artery disease (n = 28) [279] | Human | ↓ hsCRP levels Induced leukocyte activation |
| Animal studies | |||
| Stem cells | ApoE−/− mice [288] | Mouse | Anti-inflammatory effect by reduced IFN-γ, IL-6, and TNF-α expression ↓ VLDL, circulating monocytes, and serum CCL2 levels |
| Simvastatin | Rabbit model of atherosclerosis [215] | Rabbit | Induced atheroma regression ↓ MMP activity Pronounced reduction in plaque size with simvastatin plus selective PPARγ agonist |
| Alirocumab | APOE∗3Leiden.CETP transgenic mice [246] | Mouse | Inhibited PCSK9 receptor ↓ TC and TG plasma levels Improved plaque morphology ↓ ICAM-1 and monocyte adhesion |
| Febuxostat | ApoE−/− mice [70] | Mouse | Inhibited xanthine oxidase Suppressed plaque formation ↓ MCP-1, IL-1α, and IL-1β ↑ eNOS mRNA levels |
| Mitoquinone | ATM+/+/ApoE–/– and ATM+/–/ApoE–/– mice [295] | Mouse | ↑ mitochondrial antioxidant Prevented the increase of adiposity, hypercholesterolemia, and hypertriglyceridemia ↓ macrophage content and cell proliferation within plaques |
| Mito-esc | ApoE−/− mice [296] | Mouse | Reduced plaque in thoracic and abdominal aorta ↓ monocyte/macrophage infiltration, ICAM-1, and CD45.2 levels |
| PEG-b-PPS micelles | Ldlr −/− female mice and RAW blue cells [300] | Mouse | Celastrol-loaded micelles reduced NF-κB signalling and TNF-α secretion ↓inflammatory cells such neutrophils, monocytes and natural killer cells, and plaque area |
| Decitabine | Ldlr−/− mice [307] | Mouse | Inhibited DNA methylation Downregulated expression of inflammatory genes (TNF-α, IL-6, IL-1β, and iNOS) ↓ macrophage migration and infiltration into atherosclerotic plaques |
| Hydralazine | C57/BL6 mouse model of Ang II infusion [309] | Mouse | Inhibited DNA methylation Blocked Ang II-induced fibrosis ↓ inflammatory cell infiltration and proinflammatory cytokine expression |
| Curcumin | ApoE–/– mice [274] | Mouse | Reduced TLR4 expression and macrophage infiltration in atherosclerotic plaques ↓ TNF-α, IL-1β, VCAM-1, and ICAM-1 expression and plasma levels, and NF-κB activity |
| Vorinostat | BALB/c mice [313] | Mouse | Inhibited HDACs Reduction of circulating TNF-α, IL-1β, IL-6, and IFN-γ induced by lipopolysaccharide |
| Valproate | Hyperglycaemic ApoE−/− mice [314] | Mouse | Inhibited HDACs Attenuated endoplasmic reticulum stress response genes Decreased in cross-sectional lesion area of atherosclerotic lesion |
| Cell culture studies | |||
| Aspirin | Platelets from healthy patients (n = 27) [195] | Human | Inhibited COX-1 ↓ the expression of platelet receptors (GPIIb/IIIa, P-selectin) and natural killer cell markers (CD107a and CD63) |
| Simvastatin | Cell culture of mesangial cells [214] | Human | ↓ Ang II-induced inflammation and oxidative stress via COX-2, PPARγ, NF-κB, Nox, and PKC |
| Rosuvastatin | Cell culture of peripheral blood mononuclear cells [213] | Human | Promoted M2 macrophage phenotype ↑ PPARγ mRNA expression ↓ TNF-α and MCP-1 levels |
| Mito-esc | Human aortic endothelial cells [296] | Human | Inhibited H2O2 and Ang II-induced cell death Promoted mitochondrial biogenesis by enhancing SIRT3 expression |
| Azacytidine and RG108 | Human aortic endothelial cells [306] | Human | Inhibited DNMT3A Restored KLF4 pre-mRNA to undisturbed flow levels |
↑: increased; ↓: decreased; NO: nitric oxide; PCSK9: proprotein convertase subtilisin/kexin type 9; LDL: low-density lipoprotein; IL: interleukin; ET: endothelin; hsCRP: high-sensitivity C-reactive protein; TNF-α: tumour necrosis factor α; VLDL: very low-density lipoprotein; MMPs: matrix metalloproteinases; ICAM-1: intercellular adhesion molecule 1; MCP-1: monocyte chemotactic protein-1; eNOS: endothelial nitric oxide synthase; NF-κB: nuclear factor κB; iNOS: inducible nitric oxide synthase; Ang II: angiotensin-II; TLR4: Toll-like receptor 4; VCAM-1: vascular cell adhesion molecule 1; HDAC: histone deacetylases; Nox: NADPH oxidases; PKC: protein kinase C; DNMT3A: DNA methyltransferase 3A.