Flow signaling and atherosclerosis

Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be athero-protective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow. The ability of ECs to differentially respond to the two types of flow provides an opportunity to identify molecular events that lead to endothelial dysfunction and atherosclerosis. In this review, we will focus on various molecular events, which are differentially regulated by these two flow types. We will discuss how various kinases, ER stress, inflammasome, SUMOylation, and DNA methylation play roles in the differential flow response, endothelial dysfunction, and atherosclerosis. We will also discuss the interplay among the molecular events and how they coordinately regulate flow-dependent signaling and cellular responses. It is hoped that clear understanding of the way how the two flow types beget each unique phenotype in ECs will lead us to possible points of intervention against endothelial dysfunction and cardiovascular diseases.     

Integrin antagonists

Integrins are a family of cell surface glycoproteins that mediate numerous cell-cell and cell-matrix interactions and are involved in biological processes such as tissue morphogenesis, leukocyte recirculation and migration, wound healing, blood clotting and immune response. Aberrant cell adhesion has been implicated in the pathogenesis of several diseases, including a number of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease and asthma, as well as cancer and coronary heart disease. As such integrins are seen as excellent targets for the development of therapeutic agents. This report begins with an examination of the structure of integrin molecules and their ligands and then goes on to review the current state of development of antiintegrin antagonists. Received 13 April 1999; received after revision 28 May 1999; accepted 28 May 1999     

RGD在整合素中的作用及纤粘蛋白介导的生物学过程

整合素直接参与细胞与细胞质的相互作用,控制细胞的分化、形态发生、增殖和迁徙。整合素直接参与细胞与细胞质的相互作用受到细胞粘附分子整合素家族的调节,以增强它们的粘附功能。整合素受体功能被认为是细胞行为的关键调节器。在再生性血管中选择性表达的许多分子中,整合素在肿瘤靶向方面显示出了特别的希望。SaiKi和其合作者报告．肿瘤再生血管受到整合素和含有精氨酸-甘氨酸-天冬氨酸（RGD）序列的细胞质蛋白的相互作用而受到抑制。在再生性心血管形成中研究最多之一的靶向决定簇是αvβ3整合素。研究表明αvβ3和αvβ5整合素更能调节血管再生内皮细胞,并且这些整合素受到抗体的抑制,环RGD肽和RGD多肽类似物能干扰新血管的形成。本文意在概括一下RGD在整合素中的作用及纤粘蛋白介导的生物过程。     

Integrin and microtubule crosstalk in the regulation of cellular processes

Integrins engage components of the extracellular matrix, and in collaboration with other receptors, regulate signaling cascades that impact cell behavior in part by modulating the cell’s cytoskeleton. Integrins have long been known to function together with the actin cytoskeleton to promote cell adhesion, migration, and invasion, and with the intermediate filament cytoskeleton to mediate the strong adhesion needed for the maintenance and integrity of epithelial tissues. Recent studies have shed light on the crosstalk between integrin and the microtubule cytoskeleton. Integrins promote microtubule nucleation, growth, and stabilization at the cell cortex, whereas microtubules regulate integrin activity and remodeling of adhesion sites. Integrin-dependent stabilization of microtubules at the cell cortex is critical to the establishment of apical–basal polarity required for the formation of epithelial tissues. During cell migration, integrin-dependent microtubule stabilization contributes to front–rear polarity, whereas microtubules promote the turnover of integrin-mediated adhesions. This review focuses on this interdependent relationship and its impact on cell behavior and function.     

Proteins and atherosclerosis

Résumé Les examens macroscopiques et microscopiques effectués sur l'aorte des lapins ont été mis en corrélation avec le degré de concentration de la protéine plasmique. Les résultats indiquent qu'une augmentation des protéines plasmiques correspond a un degré plus élevé d'athérosclérose.     

Type VI collagen in experimental atherosclerosis

Summary Diffuse intercellular immunofluorescence staining of type VI collagen was found in the experimentally thickened vascular wall and in control blood vessel tissues as well, superimposed by more intense staining around basement membranes. While the basement membrane staining disappeared in advanced mural thickenings, the diffusely distributed network of type VI collagen remained.     

Type VI collagen in experimental atherosclerosis

Diffuse intercellular immunofluorescence staining of type VI collagen was found in the experimentally thickened vascular wall and in control blood vessel tissues as well, superimposed by more intense staining around basement membranes. While the basement membrane staining disappeared in advanced mural thickenings, the diffusely distributed network of type VI collagen remained.     

Inflammation and immune system interactions in atherosclerosis

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16.7 million deaths each year. The underlying cause of the majority of CVD is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. Today’s picture is far more complex. Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries. Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis. By transforming immune cells into pro- and anti-inflammatory chemokine- and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke. In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis.     

The use of crocetin in experimental atherosclerosis

Résumé L'action préventive de la crocetine de l'apparition de l'artério-sclerose sur l'aorte du lapin soumis à un régime hypercholestérolémiant est démontrée. Par contre le mécanisme d'action de cette substance n'est pas élucidé par les expériences relatées.     

Calcium signaling in plants

Changes in the cytosolic concentration of calcium ions ([Ca²⁺]_i) play a key second messenger role in signal transduction. These changes are visualized by making use of either Ca²⁺-sensitive fluorescent dyes or the Ca²⁺-sensitive photoprotein, aequorin. Here we describe the advances made over the last 10 years or so, which have conclusively demonstrated a second messenger role for [Ca²⁺]_i in a few model plant systems. Characteristic changes in [Ca²⁺]_i have been seen to precede the responses of plant cells and whole plants to physiological stimuli. This has had a major impact on our understanding of cell signaling in plants. The next challenge will be to establish how the Ca²⁺ signals are encrypted and decoded in order to provide specificity, and we discuss the current understanding of how this may be achieved.     

Triglycerides and other lipid classes in human atherosclerosis

Riassunto I lipidi totali e le singole classi lipidiche sono stati determinati sul plasma di 15 soggetti normali e di 25 aterosclerotici. I lipidi totali e i trigliceridi plasmatici sono risultati, in modo statisticamente significativo, più alti nei soggetti aterosclerotici. I trigliceridi inoltre sono risultati più elevati negli aterosclerotici, anche quando erano espressi come percentuale dei lipidi totali. I trigliceridi sembrano essere la classe lipidica più significativa nella malattia aterosclerotica.     

Ion channels in plant signaling

Plant ion channel activities are rapidly modulated in response to several environmental and endogenous stimuli such as light, pathogen attack and phytohormones. Electrophysiological as well as pharmacological studies provide strong evidence that ion channels are essential for the induction of specific cellular responses, implicating their tight linkage to signal transduction cascades. Ion channels propagate signals by modulating the membrane potential or by directly affecting cellular ion composition. In addition, they may also be effectors at the end of signaling cascades, as examplified by ion channels which determine the solute content of stomatal guard cells. Plant channels are themselves subject to regulation by a variety of cellular factors, including calcium, pH and cyclic nucleotides. In addition, they appear to be regulated by (de)-phosphorylation events as well as by direct interactions with cytoskeletal and other cellular proteins. This review summarizes current knowledge on the role of ion chan nels in plant signaling.     

Histone deacetylase signaling in cardioprotection

Cardiovascular disease (CVD) represents a major challenge for health care systems, both in terms of the high mortality associated with it and the huge economic burden of its treatment. Although CVD represents a diverse range of disorders, they share common compensatory changes in the heart at the structural, cellular, and molecular level that, in the long term, can become maladaptive and lead to heart failure. Treatment of adverse cardiac remodeling is therefore an important step in preventing this fatal progression. Although previous efforts have been primarily focused on inhibition of deleterious signaling cascades, the stimulation of endogenous cardioprotective mechanisms offers a potent therapeutic tool. In this review, we discuss class I and class II histone deacetylases, a subset of chromatin-modifying enzymes known to have critical roles in the regulation of cardiac remodeling. In particular, we discuss their molecular modes of action and go on to consider how their inhibition or the stimulation of their intrinsic cardioprotective properties may provide a potential therapeutic route for the clinical treatment of CVD.     

Influence of vitamin A on experimental atherosclerosis in rabbits

Résumé La vitamine A a eu un effet hypocholestérimique modéré (7 à 43%) sur des lapins nourris de 0.2% cholestérol. La gravité de l'athérosclérose moyenne fut réduite de 31% dans la crosse aortique, et de 61% dans l'aorte abdominale. L'administration de vitamine A aux lapins nourris de cholésterol a réduit les niveaux de sérum -glucuronidase d'une manière significative, il est donc possible que cette vitamine ait une influence stabilisatrice sur le lysosome.     

3-Hydroxy-3-methylglutaric acid and experimental atherosclerosis in rats

Summary In rats 3-hydroxy-3-methylglutaric acid effectively counteracts the lipemic and atherosclerotic response of massive doses of vitamin D₂. It regressed the formation of atheromatous arterial lesions. Furthermore the significant decrease in serum -lipoprotein levels on HMG treatment could be due to decrease in VLDL triglyceride and cholesterol levels.Acknowledgments. The authors are indebted to Dr.W. Drell, President, Calbiochem, San Diego, California, USA, for generous gift of HMG and Lady Tata Memorial Trust, India, for providing financial assistance to one of us (S.Y.K.Y.).