Pro-Calcifying Role of Enzymatically Modified LDL (eLDL) in Aortic Valve Sclerosis via Induction of IL-6 and IL-33.

One of the contributors to atherogenesis is enzymatically modified LDL (eLDL). eLDL was detected in all stages of aortic valve sclerosis and was demonstrated to trigger the activation of p38 mitogen-activated protein kinase (p38 MAPK), which has been identified as a pro-inflammatory protein in atherosclerosis. In this study, we investigated the influence of eLDL on IL-6 and IL-33 induction, and also the impact of eLDL on calcification in aortic valve stenosis (AS).

C-Reactive Protein: Friend or Foe? Phylogeny From Heavy Metals to Modified Lipoproteins and SARS-CoV-2.

Animal C-reactive protein (CRP) has a widespread existence throughout phylogeny implying that these proteins have essential functions mandatory to be preserved. About 500 million years of evolution teach us that there is a continuous interplay between emerging antigens and components of innate immunity. The most archaic physiological roles of CRP seem to be detoxication of heavy metals and other chemicals followed or accompanied by an acute phase response and host defense against bacterial, viral as well as parasitic infection.

The Initial Human Atherosclerotic Lesion and Lipoprotein Modification-A Deep Connection.

Atherosclerosis research typically focuses on the evolution of intermediate or advanced atherosclerotic lesions rather than on prelesional stages of atherogenesis. Yet these early events may provide decisive leads on the triggers of the pathologic process, before lesions become clinically overt. Thereby, it is mandatory to consider extracellular lipoprotein deposition at this stage as the prerequisite of foam cell formation leading to a remarkable accumulation of LDL (Low Density Lipoproteins).

Novel Blood Biomarkers for a Diagnostic Workup of Acute Aortic Dissection.

Acute aortic dissection (AAD) is a rare condition, but together with acute myocardial infarction (AMI) and pulmonary embolism (PE) it belongs to the most relevant and life-threatening causes of acute chest pain. Until now, there has been no specific blood test in the diagnostic workup of AAD. To identify clinically relevant biomarkers for AAD, we applied Proseek Multiplex assays to plasma samples from patients with AAD, AMI, PE, thoracic aortic aneurysm (TAA), and non-cardiovascular chest pain (nonCVD).

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.

Objective: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).

Methods: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial.

Fibroblasts and Their Pathological Functions in the Fibrosis of Aortic Valve Sclerosis and Atherosclerosis.

Cardiovascular diseases, such as atherosclerosis and aortic valve sclerosis (AVS) are driven by inflammation induced by a variety of stimuli, including low-density lipoproteins (LDL), reactive oxygen species (ROS), infections, mechanical stress, and chemical insults. Fibrosis is the process of compensating for tissue injury caused by chronic inflammation. Fibrosis is initially beneficial and maintains extracellular homeostasis.

Role of p38 MAPK in Atherosclerosis and Aortic Valve Sclerosis.

Atherosclerosis and aortic valve sclerosis are cardiovascular diseases with an increasing prevalence in western societies. Statins are widely applied in atherosclerosis therapy, whereas no pharmacological interventions are available for the treatment of aortic valve sclerosis. Therefore, valve replacement surgery to prevent acute heart failure is the only option for patients with severe aortic stenosis.

Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis.

The gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets were categorized pathologically from Both ATX-apoB and ATX-apo(a) were measureable in plasma.

Enzymatically modified LDL, atherosclerosis and beyond: paving the way to acceptance.

The eLDL (enzymatically modified LDL) hypothesis proposes that modification of LDL during atherogenesis occurs through the action of ubiquitous hydrolytic enzymes. eLDL is recognized by multiple macrophage receptors. Following cellular uptake, eLDL triggers atherosclerotic lesion initiation with reversion or progression depending on the balance between cholesterol insudation and depletion.

Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.

The first ATP-competitive p38α MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38α MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38α/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes.

Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice.

This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr-/- Rag1-/- mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr-/- Rag1-/- Il2rg-/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western type diet (WTD).

Enzymatically Modified Low-Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease.

Background: We have demonstrated previously that enzymatically degraded low-density lipoprotein (eLDL) is an essential causative component for the initiation of atherosclerosis. Here, we investigated the different stages of human aortic valve sclerosis for the presence of eLDL and effectors of the innate immune system, as well as the interaction of eLDL with isolated valvular interstitial cells/myofibroblasts to discover possible pathways leading to aortic valve sclerosis.

Methods And Results: Human aortic valvular tissue was obtained from 68 patients undergoing valve replacement surgery.

Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis.

The digestive vacuole (DV) of Plasmodium falciparum, which is released into the bloodstream upon rupture of each parasitized red blood cell (RBC), was recently discovered to activate the alternative complement pathway. In the present work, we show that C3- and C5-convertases assembling on the parasitic organelle are able to provoke deposition of activated C3 and C5b-9 on non-infected bystander erythrocytes. Direct contact of DVs with cells is mandatory for the effect, and bystander complement deposition occurs focally, possibly at the sites of contact.

Animal models of C-reactive protein.

As the main theme of this special issue, CRP not only is an inflammatory marker but also has diverse biological functions associated with different diseases. To investigate CRP's physiologies and their relationship with human pathological significance, it is essential to use appropriate animal models for translational research. The most popular models for the study of CRP are transgenic mice.

T cell-specific overexpression of TGFß1 fails to influence atherosclerosis in ApoE-deficient mice.

Clinical data have indicated a negative correlation between plasma TGFß1 concentrations and the extent of atherosclerosis and have thus led to the hypothesis that the pleiotropic cytokine may have anti-atherogenic properties. T-cells are currently discussed to significantly participate in atherogenesis, but the precise role of adaptive immunity in atherogenesis remains to be elucidated. TGFß1 is known to strongly modulate the function of T-cells, however, inhibition of TGFß1 signalling in T-cells of atherosclerosis-prone knock-out mice failed to unequivocally clarify the role of the cytokine for the development of atherosclerosis.

Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging.

Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1-deficient (GPx-1(-/-)) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1(-/-) mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used.

Impact of glutathione peroxidase-1 deficiency on macrophage foam cell formation and proliferation: implications for atherogenesis.

Clinical and experimental evidence suggests a protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx-1) in the atherogenic process. GPx-1 deficiency accelerates atherosclerosis and increases lesion cellularity in ApoE(-/-) mice. However, the distribution of GPx-1 within the atherosclerotic lesion as well as the mechanisms leading to increased macrophage numbers in lesions is still unknown.

Complement and atherosclerosis-united to the point of no return?

Atherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of oxidized low-density lipoprotein (LDL) in the arterial intima and its interaction with components of both innate and adaptive immunity. This article reviews the role of the complement system in the context of a different concept on atherogenesis. Arguments are forwarded in support of the contention that enzymatic and not oxidative modification of LDL is the prerequisite for transforming the lipoprotein into a moiety that is recognized by the innate immune system.

Overexpression of TGF-ß1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice.

Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-ß1 (transforming growth factor β1) and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-ß1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-ß1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E) knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE(-/-) mice, animals with macrophage specific TGF-ß1 overexpression developed significantly less atherosclerosis after 24 weeks on the WTD (Western type diet) as indicated by aortic plaque area en face (p<0.

Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation.

Severe Plasmodium falciparum malaria evolves through the interplay among capillary sequestration of parasitized erythrocytes, deregulated inflammatory responses, and hemostasis dysfunction. After rupture, each parasitized erythrocyte releases not only infective merozoites, but also the digestive vacuole (DV), a membrane-bounded organelle containing the malaria pigment hemozoin. In the present study, we report that the intact organelle, but not isolated hemozoin, dually activates the alternative complement and the intrinsic clotting pathway.

Chronic inflammatory cardiomyopathy of interferon γ-overexpressing transgenic mice is mediated by tumor necrosis factor-α.

We recently described a model of inflammatory cardiomyopathy in interferon (IFN)-γ overexpressing transgenic mice stably circulating IFN-γ in the serum referred to as SAP--IFN-γ mice. SAP-IFN-γ transgenic mice show cardiac infiltration by mononuclear leukocytes, culminating in dilated cardiomyopathy characterized by an increase of left ventricular end diastolic diameter and reduction of fractional shortening. We hypothesized that the pathological mechanism underlying SAP-IFN-γ cardiomyopathy might be mediated by (auto)immune processes or tumor necrosis factor (TNF)-α synthesis from IFN-γ-activated macrophages.

Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression.

Objectives: We sought to assess the in vivo importance of scavenger receptor (SR)-mediated uptake of oxidized low-density lipoprotein (OxLDL) in atherogenesis and to test the efficacy of human antibody IK17-Fab or IK17 single-chain Fv fragment (IK17-scFv), which lacks immunologic properties of intact antibodies other than the ability to inhibit uptake of OxLDL by macrophages, to inhibit atherosclerosis.

Background: The unregulated uptake of OxLDL by macrophage SR contributes to foam cell formation, but the importance of this pathway in vivo is uncertain.

Methods: Cholesterol-fed low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated with intraperitoneal infusion of human IK17-Fab (2.

Differential effects of heart rate reduction with ivabradine in two models of endothelial dysfunction and oxidative stress.

Heart rate reduction with the I(f)-channel-inhibitor ivabradine is a novel and appealing option in the therapy of patients with ischemic heart disease. The aim of the current study was to determine the effects of ivabradine in two different animal models of vascular disease characterized by increased oxidative stress and endothelial dysfunction. Wistar rats with angiotensin II induced hypertension and ApoE knockout mice were used as animal models of endothelial dysfunction and oxidative stress, with half of the animals receiving ivabradine 10 mg/kg/day in parallel.