Current topics in membranes最新文献

Extracellular signaling molecules, such as growth factors, cytokines, and hormones, regulate cell behaviors and fate through endocrine, paracrine, and autocrine actions and play essential roles in maintaining tissue homeostasis. MicroRNAs, an important class of posttranscriptional modulators, could stably present in extracellular space and body fluids and participate in intercellular communication in health and diseases. Indeed, recent studies demonstrated that microRNAs could be secreted through vesicular and non-vesicular routes, transported in body fluids, and then transmitted to recipient cells to regulate target gene expression and signaling events. Over the past decade, a great deal of effort has been made to investigate the functional roles of extracellular vesicles and extracellular microRNAs in pathological conditions. Emerging evidence suggests that altered levels of extracellular vesicles and extracellular microRNAs in body fluids, as part of the cellular responses to atherogenic factors, are associated with the development of atherosclerosis. This review article provides a brief overview of extracellular vesicles and perspectives of their applications as therapeutic tools for cardiovascular pathologies. In addition, we highlight the role of extracellular microRNAs in atherogenesis and offer a summary of circulating microRNAs in liquid biopsies associated with atherosclerosis.

Hypercholesterolemia is a well-known pro-atherogenic risk factor and statin is the most effective anti-atherogenic drug that lowers blood cholesterol levels. However, despite systemic hypercholesterolemia, atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while the stable flow (s-flow) regions are spared. Given their predominant effects on endothelial function and atherosclerosis, we tested whether (1) statin and flow regulate the same or independent sets of genes and (2) statin can rescue d-flow-regulated genes in mouse artery endothelial cells in vivo. To test the hypotheses, C57BL/6 J mice (8-week-old male, n=5 per group) were pre-treated with atorvastatin (10mg/kg/day, Orally) or vehicle for 5 days. Thereafter, partial carotid ligation (PCL) surgery to induce d-flow in the left carotid artery (LCA) was performed, and statin or vehicle treatment was continued. The contralateral right carotid artery (RCA) remained exposed to s-flow to be used as the control. Two days or 2 weeks post-PCL surgery, endothelial-enriched RNAs from the LCAs and RCAs were collected and subjected to microarray gene expression analysis. Statin treatment in the s-flow condition (RCA+statin versus RCA+vehicle) altered the expression of 667 genes at 2-day and 187 genes at 2-week timepoint, respectively (P<0.05, fold change (FC)≥±1.5). Interestingly, statin treatment in the d-flow condition (LCA+statin versus LCA+vehicle) affected a limited number of genes: 113 and 75 differentially expressed genes at 2-day and 2-week timepoint, respectively (P<0.05, FC≥±1.5). In contrast, d-flow in the vehicle groups (LCA+vehicle versus RCA+vehicle) differentially regulated 4061 genes at 2-day and 3169 genes at 2-week timepoint, respectively (P<0.05, FC≥±1.5). Moreover, statin treatment did not reduce the number of flow-sensitive genes (LCA+statin versus RCA+statin) compared to the vehicle groups: 1825 genes at 2-day and 3788 genes at 2-week, respectively, were differentially regulated (P<0.05, FC≥±1.5). These results revealed that both statin and d-flow regulate expression of hundreds or thousands of arterial endothelial genes, respectively, in vivo. Further, statin and d-flow regulate independent sets of endothelial genes. Importantly, statin treatment did not reverse d-flow-regulated genes except for a small number of genes. These results suggest that both statin and flow play important independent roles in atherosclerosis development and highlight the need to consider their therapeutic implications for both.

Living cells are exposed to multiple mechanical stimuli from the extracellular matrix or from surrounding cells. Mechanoreceptors are molecules that display status changes in response to mechanical stimulation, transforming physical cues into biological responses to help the cells adapt to dynamic changes of the microenvironment. Mechanical stimuli are responsible for shaping the tridimensional development and patterning of the organs in early embryonic stages. The development of the heart is one of the first morphogenetic events that occur in embryos. As the circulation is established, the vascular system is exposed to constant shear stress, which is the force created by the movement of blood. Both spatial and temporal variations in shear stress differentially modulate critical steps in heart development, such as trabeculation and compaction of the ventricular wall and the formation of the heart valves. Zebrafish embryos are small, transparent, have a short developmental period and allow for real-time visualization of a variety of fluorescently labeled proteins to recapitulate developmental dynamics. In this review, we will highlight the application of zebrafish models as a genetically tractable model for investigating cardiovascular development and regeneration. We will introduce our approaches to manipulate mechanical forces during critical stages of zebrafish heart development and in a model of vascular regeneration, as well as advances in imaging technologies to capture these processes at high resolution. Finally, we will discuss the role of molecules of the Plexin family and Piezo cation channels as major mechanosensors recently implicated in cardiac morphogenesis.

The volume-regulated anion channel (VRAC) is activated upon cell swelling and facilitates the passive movement of anions across the plasma membrane in cells. VRAC function underlies many critical homeostatic processes in vertebrate cells. Among them are the regulation of cell volume and membrane potential, glutamate release and apoptosis. VRAC is also permeable for organic osmolytes and metabolites including some anti-cancer drugs and antibiotics. Therefore, a fundamental understanding of VRAC's structure-function relationships, its physiological roles, its utility for therapy of diseases, and the development of compounds modulating its activity are important research frontiers. Here, we describe approaches that have been applied to study VRAC since it was first described more than 30 years ago, providing an overview of the recent methodological progress. The diverse applications reflecting a compromise between the physiological situation, biochemical definition, and biophysical resolution range from the study of VRAC activity using a classic electrophysiology approach, to the measurement of osmolytes transport by various means and the investigation of its activation using a novel biophysical approach based on fluorescence resonance energy transfer.

This review focuses on time-resolved neutron scattering, particularly time-resolved small angle neutron scattering (TR-SANS), as a powerful in situ noninvasive technique to investigate intra- and intermembrane transport and distribution of lipids and sterols in lipid membranes. In contrast to using molecular analogues with potentially large chemical tags that can significantly alter transport properties, small angle neutron scattering relies on the relative amounts of the two most abundant isotope forms of hydrogen: protium and deuterium to detect complex membrane architectures and transport processes unambiguously. This review discusses advances in our understanding of the mechanisms that sustain lipid asymmetry in membranes-a key feature of the plasma membrane of cells-as well as the transport of lipids between membranes, which is an essential metabolic process.

Mass spectrometry imaging (MSI) is a powerful tool for in situ mapping of analytes across a sample. With growing interest in lipid biochemistry, the ability to perform such mapping without antibodies has opened many opportunities for MSI and lipid analysis. Herein, we discuss the basics of MSI with particular emphasis on MALDI mass spectrometry and lipid analysis. A discussion of critical advancements as well as protocol details are provided to the reader. In addition, strategies for improving the detection of lipids, as well as applications in biomedical research, are presented.

To perceive and integrate the environmental cues, cells and tissues sense and interpret various physical forces like shear, tensile, and compression stress. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical and mechanical signals to guide cell fate and achieve tissue homeostasis. Disruption of this mechanical homeostasis by tissue injury elicits multiple cellular responses leading to pathological matrix deposition and tissue stiffening, and consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes, leading to tissue/organ fibrosis. This review focuses on the molecular mechanisms linking mechanotransduction to fibrosis and uncovers the potential therapeutic targets to halt or resolve fibrosis.

Cells and tissues are constantly exposed to mechanical stress. In order to respond to alterations in mechanical stimuli, specific cellular machinery must be in place to rapidly convert physical force into chemical signaling to achieve the desired physiological responses. Mechanosensitive ion channels respond to such physical stimuli in the order of microseconds and are therefore essential components to mechanotransduction. Our understanding of how these ion channels contribute to cellular and physiological responses to mechanical force has vastly expanded in the last few decades due to engineering ingenuities accompanying patch clamp electrophysiology, as well as sophisticated molecular and genetic approaches. Such investigations have unveiled major implications for mechanosensitive ion channels in cardiovascular health and disease. Therefore, in this chapter I focus on our present understanding of how biophysical activation of various mechanosensitive ion channels promotes distinct cell signaling events with tissue-specific physiological responses in the cardiovascular system. Specifically, I discuss the roles of mechanosensitive ion channels in mediating (i) endothelial and smooth muscle cell control of vascular tone, (ii) mechano-electric feedback and cell signaling pathways in cardiomyocytes and cardiac fibroblasts, and (iii) the baroreflex.