Table 1.

Oxidative stress mechanisms in cardiovascular diseases.

Pathological Condition	Relevant Oxidative Stress Mechanisms	References
Obesity	Reactive oxygen species (ROS)-induced downregulation of Nitric Oxide (NO) activity.	[10]
	Perivascular adipose tissue is responsible for tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 secretion, which sustain a low grade inflammatory state and an increased ROS production.	[11,12]
	In morbidly obese patients, arginase is up-regulated. Increased arginase activity competes with endothelial NO synthase (eNOS), whose main substrate for NO production is arginine; thus, reducing NO availability.	[13,14]
Diabetes and hyperglycemic conditions	Hyperglycemia is involved in mitochondrial generation of superoxide anion (O−.) which contributes to diabetic endothelial dysfunction through four main pathways: the polyol pathway, increase in intracellular production of advanced glycation end products (AGEs), activation of the protein-kinase C (PKC) pathway, the hexosamine pathway	[15,16]
	Hyperglycemia determines an increased ROS production that leads to mitochondrial DNA damage in endothelial cells. A so-determined increase in mitochondrial fission impairs electron-transport chain, which causes an altered nicotinamide adenine dinucleotide phosphate (NADH)\ flavin adenine dinucleotide (FADH2) ratio	[17]
	Hyperglycemia triggers a chronic vascular inflammatory state sustained by TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), cluster of differentiation 36 (CD36), monocyte chemoattractant protein-1 (MCP-1), and mediated through the up-regulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which leads to endothelial cell apoptosis.	[18,19]
	In the pathogenesis of diabetes, an altered expression of several microRNAs has been demonstrated. A reduced lethal-7 (let-7) microRNA (miRNA) and miR-126 expression and an increased miR-200 expression have been linked to β-cells impairment, insulin resistance, chronic inflammation, and vascular oxidative stress.	[20,21,22,23]
	Insulin resistance is generated by ROS mediated activation of several pathways, such as p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), IkB kinase (IKK). These pathways converge on phosphorylation of insulin receptor substrate proteins, which determine alterations in insulin signal transmission.	[24,25]
	High insulin levels upregulate the MAPK pathway, which is involved in plaque formation and vascular smooth muscle cells (VSMC) hypertrophy and proliferation.	[26]
Dysmetabolic conditions	ROS have been associated to low-density lipoproteins (LDL) oxidation, generating oxidized low-density lipoproteins (ox-LDL), which are removed from the systemic circulation by binding to scavenger receptor on macrophage surface. This elicits inflammatory response through NF-κB pathway and determines formation of foam cells.	[27,28]
	Ox-LDLs drive caspase activation and endothelial cell apoptosis.	[29]
	Hyperuricemia contributes to endothelial dysfunction mainly through NO depletion. The reaction between uric acid (UA) and NO generates 6-aminouracil, thus, reducing NO availability. UA is also responsible for increased arginine degradation which is the main eNOS substrate for NO synthesis.	[30]
Cigarette Smoke	Cigarette smoke (CS) is a suppressor of endothelial NO synthase eNOS and determines reduction in NO bioavailability. It is also responsible for ROS production, tissue remodeling, and increased expression of adhesion molecules and prothrombotic factors.	[31]
Hypertension	Chronic inflammation produces inflammatory chemokines, such as IL-6, IL-1β, TNF-α, and interleukin-17 (IL-17), which promote oxidative stress and recruit macrophages, T and B lymphocytes that are responsible for ROS production and vascular fibrotic remodeling.	[32,33]
	Damage to the endothelial cells that release increased levels of endothelial microparticles (EMP), which causes an impaired glomerular filtration rate and is implicated in vascular inflammation, thrombosis, angiogenesis, and atherosclerosis progression.	[34,35]
	Hypertensive inflammation induces NADPH oxidases (Nox), one of the most important sources of superoxide anion (O−) in endothelial dysfunction. Superoxide anion react with NO forming peroxynitrite, which oxidizes the 4-tetrahydrobiopterin (BH4), a cofactor of eNOS; thus, determining the uncoupling of eNOS and a decreased NO bioavailability.	[36,37]
	NO is able to modulate response to angiotensin II and to invert angiotensin II-induced arteriolar contraction.	[38]
	Aldosterone has proinflammatory effects that are mediated through the mineralocorticoid receptor (MR). Aberrant activation of MR mediates endothelial and organ damage, directly, or through angiotensin 1.	[39,40]
Aging	Endothelium-dependent dilation (EDD) is decreased with aging because of a reduced NO bioavailability. NO production in older adults are reduced under baseline resting conditions.	[41]
	Aging increases the production of reactive oxygen species in the face of unchanged or reduced antioxidant defenses.	[41]
	Age-related endothelial redox changes affect NF-kB, whose activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus, creating a vicious feed-forward cycle.	[42]
	Genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults.	[42]