Major reactive oxygen species (ROS)-producing systems in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase. ROS at moderate concentrations have important signaling roles under physiological conditions. Excessive or sustained ROS production, however, when exceeding the available antioxidant defense systems, leads to oxidative stress. Animal studies have provided compelling evidence demonstrating the roles of vascular oxidative stress and NO in atherosclerosis. All established cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and smoking enhance ROS generation and decrease endothelial NO production. Key molecular events in atherogenesis such as oxidative modification of lipoproteins and phospholipids, endothelial cell activation, and macrophage infiltration/activation are facilitated by vascular oxidative stress and inhibited by endothelial NO. Atherosclerosis develops preferentially in vascular regions with disturbed blood flow (arches, branches, and bifurcations). The fact that these sites are associated with enhanced oxidative stress and reduced endothelial NO production is a further indication for the roles of ROS and NO in atherosclerosis. Therefore, prevention of vascular oxidative stress and improvement of endothelial NO production represent reasonable therapeutic strategies in addition to the treatment of established risk factors (hypercholesterolemia, hypertension, and diabetes mellitus).

Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis

The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG I...

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Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology.

Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clin...

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Clinical Relevance of Biomarkers of Oxidative Stress

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

Inflammation, Immunity, and Hypertensive End-Organ Damage

Age-related decline in function is a physiological phenomenon occurring in all organ systems. However, acceleration and early occurrence of this process are observed in cardiovascular pathologies, including hypertension.1,2 In the vascular system, this is characterized by progressive pathological remodeling with stiffening,3 typically associated with extracellular matrix (ECM) alterations in collagen and elastin.4 This is, in part, dependent on cellular senescence and growth arrest.5 Although hypertension and atherosclerosis are associated with accumulation of cellular senescence markers in the vascular wall, these conditions are often associated with vascular dysfunction rather than simple loss of proliferative capacity.6 For example, risk factors for cardiovascular disease, such as hypertension, smoking, hyperlipidaemia, or diabetes mellitus are associated with accelerated decline of vascular function.2 This is why vascular age determination has been introduced in key clinical guidelines for cardiovascular prevention, to indicate to the patient how their lifestyle contributes to the acceleration of vascular function deterioration.7

Oxidative stress and inflammation, key mechanisms of endothelial dysfunction and arterial damage, link these risk factors to vascular disease, arterial stiffness, and aging. These underlie macro- and microangiopathy, renal dysfunction, cardiac ischemia, and cognitive decline (Figure). Several novel pathways regulating these mechanisms of accelerated vascular aging have been elucidated in recent issues of Hypertension and are further discussed in the present Best Papers in Hypertension review.



Figure. 
Central role of oxidative stress in accelerated vascular aging in hypertension. AT1R indicates angiotensin II receptor type 1; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; BMP, bone morphogenic protein; CypD, cyclophilin D; eNOS, endothelial NO synthase; ET1R, endothelin 1 receptor; H2O2, hydrogen peroxide; MMP, matrix metalloproteinase; Nox, NADPH oxidase; O2−., superoxide anion; RANTES, regulated on activation, normal T cell expressed and secreted chemokine; and SmgGDS, GTP-binding protein dissociation …

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension.

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.

Christi L Galindo

Papers

DC isoketal-modified proteins activate T cells and promote hypertension