Vascular aging is a crucial risk factor for atherosclerotic ischemic stroke. Vascular aging is characterized by oxidative stress, endothelial dysfunction, inflammation, intimal and media thickening, as well as the gradual development of arterial stiffness, among other pathophysiological features. Regarding oxidative stress, increased concentration of reactive oxygen and nitrogen species is linked to atherosclerotic ischemic stroke in vascular aging. Additionally, oxidative stress is associated with an inflammatory response. Inflammation is related to aging through the “inflammaging” theory, which is characterized by decreased ability to cope with a variety of stressors, in combination with an increased pro-inflammatory state. Vascular aging is correlated with changes in cerebral arteries that are considered predictors of the risk for atherosclerotic ischemic stroke. The aim of the present review is to present the role of oxidative stress and inflammation in vascular aging, as well as their involvement in atherosclerotic ischemic stroke.

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), also named as platelet-activating factor (PAF)-acetylhydrolase, exhibits a Ca²⁺-independent phospholipase A₂ activity and catalyzes the hydrolysis of the ester bond at the sn-2 position of PAF and oxidized phospholipids (oxPL). These phospholipids are formed under oxidative and inflammatory conditions, and may play important roles in atherogenesis. The vast majority of plasma Lp-PLA₂ mass binds to low-density lipoprotein (LDL) while a smaller amount is associated with high-density lipoprotein (HDL). Lp-PLA₂ is also bound to lipoprotein (a) [Lp(a)], very low-density lipoprotein (VLDL) and remnant lipoproteins. Several lines of evidence suggest that the role of plasma Lp-PLA₂ in atherosclerosis may depend on the type of lipoprotein particle with which this enzyme is associated. Data from large Caucasian population studies have supported plasma Lp-PLA₂ (primarily LDL-associated Lp-PLA₂) as a cardiovascular risk marker independent of, and additive to, traditional risk factors. On the contrary, the HDL-associated Lp-PLA₂ may express antiatherogenic activities and is also independently associated with lower risk for cardiac death. The present review presents data on the biochemical and enzymatic properties of Lp-PLA₂ as well as its structural characteristics that determine the association with LDL and HDL. We also critically discuss the possible pathophysiological and clinical significance of the Lp- PLA₂ distribution between LDL and HDL in human plasma, in view of the results of prospective epidemiologic studies on the association of Lp-PLA₂ with future cardiovascular events as well the recent studies that evaluate the possible effectiveness of specific Lp-PLA₂ inhibitors in reducing residual cardiovascular risk.

Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A₂ (Lp-PLA₂) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA₂ activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA₂ activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA₂ and the Lp-PLA₂ associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA₂ activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA₂ activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA₂ activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients.