Lipoprotein(a) is associated with DNA damage in patients with heterozygous familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients.

New possible pharmacological targets for statins and ezetimibe.

Statin therapy is the gold standard in the treatment of dyslipidemia. Understanding the mechanisms of action of these drugs provides an opportunity to define new therapeutic goals for pharmacotherapy in patients with atherosclerotic lesions. The present review indicates the existence of previously unknown therapeutic targets for statins, such as Krüppel-like Factor 2 (KLF-2), Cystathionine γ lyase (CSE) and the microRNA regulating eNOS activity and synthesis; nuclear PXR receptor and EB transcription factor regulating Inflammasome NLRP3 activity; the Dickkopf-related protein 1 (DKK-1), which inhibits the WNT signalling pathway; the peroxisome proliferator-activated receptor (PPAR-γ) in vascular smooth muscle cells (VSMCs), which regulates the cell cycle, and the ERK5-Nrf2 pathway, which reduces the level of harmful advanced glycation end-products (AGE) in VSMCs during diabetic vasculopathy. Importantly, our review includes a number of promising discoveries, specifically those related to the effects of miR-221, miR-222 and miR-27b on the structure, synthesis and activity of eNOS, such as microRNA-based therapies, which offer promise in future targeted therapies. In contrast to numerous experiments confirming the pleiotropic effect of statins, there is still insufficient evidence on the pleiotropic effect of ezetimibe, which goes beyond its basic inhibitory effect on intestinal cholesterol absorption. However, recent studies indicate that this effect is limited to inhibiting macrophage migration, decreasing VCAM-1 expression and reducing the levels of reactive oxygen species. Defining new therapeutic goals for pharmacotherapy in patients with atherosclerotic lesions and ensuring effective treatment of dyslipidemia and its associated cardiovascular complications requires a thorough understanding of both the mechanisms of action of these drugs and of atherosclerosis itself.

IL-22 modulates inflammatory properties of human primary aortic smooth muscle cells.

BACKGROUND: IL-22 is expressed at barrier surfaces, which suggests its critical role in the maintenance of normal barrier homeostasis and tissue repair. IL-22 can both promote pathological inflammation and prevent the destruction of tissues. The functional outcomes of IL-22 on vascular smooth muscle cells, which are shown to regulate immune processes within the vascular wall and which are involved in certain pathologies, have not been analyzed. OBJECTIVES: The effect of IL-22 on the expression of novel antiand pro-inflammatory and barrier disrupting cytokines, apoptosis and the expression of adhesive molecules in human primary aortic smooth muscle cells (AoSMC) was investigated. MATERIAL AND METHODS: Human AoSMC were induced with IL-22 for 24 h in vitro. The influence of IL-22 on IL-35 subunits EBI3 and p35, IL-33, IFN-γ and VEGF mRNA expression in Ao-SMC were assessed using real-time PCR. Additionally, the surface expression of ICAM-1 and apoptosis of AoSMC were analyzed in the flow cytometer. RESULTS: IL-22 caused a 2- and 3-fold increase of mRNA expression of the EBI3 and p35 IL-35 subunits, and a 40% decrease of IL-33 mRNA expression in AoSMC. Additionally, IL-22 decreased ICAM-1 expression on the surface of AoSMC by 30%. However, IL-22 affected neither IFN-γ and VEGF mRNA expression in AoSMC nor their apoptosis and viability. CONCLUSIONS: Our data suggest that IL-22, which is released by Th22 and NK cells, may be an agent affecting the inflammatory response of AoSMC, and thus it may regulate immune homeostasis of the vascular wall.