Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation

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 () [204]	Human	P2Y12 receptor antagonist; ↓ CD40L and RANTES plasma levels
Atorvastatin	Internal mammary artery from patients scheduled for coronary artery bypass graft surgery () [211]	Human	Improved vascular NO bioavailability; ↓ the production of vascular O2^−
Evolocumab	Prospective, nonrandomized study in patients with heterozygous familial hypercholesterolemia () [235]	Human	Inhibited PCSK9 receptor; ↓ LDL and apolipoprotein B levels
Anakinra	Double-blind randomized study in patients with rheumatoid arthritis () [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 () [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 () [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 () [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	APOE3Leiden.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 () [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.