Sulfate-reducing bacteria belonging to the genus Desulfotomaculum utilized inorganic pyrophosphate as a source of energy for growth in the presence of fixed carbon (acetate and yeast extract) and sulfate. Pyrophosphate does not support the growth of Desulfovibrio under the same growth conditions. Over a limited range of concentrations, growth is proportional to pyrophosphate, and extracts of bacteria grown on pyrophosphate medium have enzymatic activities similar to extracts prepared from bacteria grown on medium containing lactate plus sulfate. The variety of cell types observed in crude anaerobic pyrophosphate-enrichment cultures from a marine environment suggests that this unique type of energy metabolism is not restricted to the sulfate-reducing bacteria of the genus Desulfotomaculum.
Serving as the cell’s key interface in communicating with the outside world, primary cilia have emerged as an area of multidisciplinary research interest over the last 2 decades. Although the term “ciliopathy” was first used to describe abnormal cilia caused by gene mutations, recent studies focus on abnormalities of cilia that are found in diseases without clear genetic antecedents, such as obesity, diabetes, cancer, and cardiovascular disease. Preeclampsia, a hypertensive disease of pregnancy, is intensely studied as a model for cardiovascular disease partially due to many shared pathophysiologic elements, but also because changes that develop over decades in cardiovascular disease arise in days with preeclampsia yet resolve rapidly after delivery, thus providing a time-lapse view of the development of cardiovascular pathology. As with genetic primary ciliopathies, preeclampsia affects multiple organ systems. While aspirin delays the onset of preeclampsia, there is no cure other than delivery. The primary etiology of preeclampsia is unknown; however, recent reviews emphasize the fundamental role of abnormal placentation. During normal embryonic development, trophoblastic cells, which arise from the outer layer of the 4-day-old blastocyst, invade the maternal endometrium and establish extensive placental vascular connections between mother and fetus. In primary cilia of trophoblasts, Hedgehog and Wnt/catenin signaling operate upstream of vascular endothelial growth factor to advance placental angiogenesis in a process that is promoted by accessible membrane cholesterol. In preeclampsia, impaired proangiogenic signaling combined with an increase in apoptotic signaling results in shallow invasion and inadequate placental function. Recent studies show primary cilia in preeclampsia to be fewer in number and shortened with functional signaling abnormalities. Presented here is a model that integrates preeclampsia lipidomics and physiology with the molecular mechanisms of liquid–liquid phase separation in model membrane studies and the known changes in human dietary lipids over the last century to explain how changes in dietary lipids might reduce accessible membrane cholesterol and give rise to shortened cilia and defects in angiogenic signaling, which underlie placental dysfunction of preeclampsia. This model offers a possible mechanism for non-genetic dysfunction in cilia and proposes a proof-of-concept study to treat preeclampsia with dietary lipids.
Discerning meaningful patterns in lipidomic studies of metabolic diseases is daunting. Consideration of changes in dietary lipids over the last 150 years and the effects of this variance on membrane raft formation provides a tool to better understand lipidomic data. In vitro, mixtures of low and high melting point lipids and cholesterol spontaneously form bilayers with heterologous areas of differing order, composition, and physical properties. Through dozens of studies, the general behavior of different lipid mixtures in phase separation has been mapped and displayed as ternary lipid mixture phase diagrams; areas that show both liquid order (Lo) and liquid disorder (Ld) allow raft formation (Figure 1). In vivo, ordered membrane areas composed of sterols, sphingolipids and proteins provide platforms necessary for a complex network of cellular signaling. Although there is controversy regarding the primacy of lipids versus proteins in organizing these signaling rafts, this perspective focuses on the role that variations in dietary lipids might play in raft formation. Comparison of dietary lipids in humans living before the agricultural revolution to those living in 21st century developed areas reveals major differences. Modern diets have: increased polyunsaturated fatty acids (PUFA) from vegetable oils, an increased ratio of omega 6:3 PUFA, increased trans fatty acids (TFA), and decreased cholesterol. Plotting these variations in dietary lipids on a ternary graph provides a framework to understand the theoretical effect of dietary lipid variance on phase separation and membrane behavior. For example, how might increased dietary TFA, a widely recognized risk factor in cardiovascular disease, disrupt raft formation? Substitution of TFA for PUFA at sn‐2 in low melting point phospholipids would raise the melting point; substitution at sn‐1 on sphingolipids would lower the melting point. Because disparity in the order of membrane domains is critical in the maintenance of phase separation, convergence of melting points of these compounds would thus impede raft formation (Figure 2). To compensate, incorporation of highly unsaturated PUFA to lower the melting point of non raft phospholipids, or incorporation of longer chain saturated fatty acids to raise the melting point of raft associated lipids would restore order differential and allow raft formation, but would require other changes to maintain optimal membrane viscosity. Elevated membrane PUFA increases oxidative damage and an elevated omega 6:3 ratio increases thrombosis and inflammation. Compared to cis forms, TFA phospholipids require eight times more cholesterol to be incorporated into a membrane; with reduced cholesterol diets, accommodation of TFAs into membranes would require stimulation of endogenous cholesterol synthesis. Increased membrane cholesterol also decreases permeability to oxygen. Because most fatty acids are incorporated into cell membranes unmodified from the form in which they were absorbed from the GI tract, changes in dietary lipids critically ...
Background and AimsHypertension is a potent risk factor for coronary artery disease. The contributing mechanism however, remains elusive. We hypothesise that high intraluminal pressure per se induces vascular infl ammation and the adhesion cascade. Methods and ResultsUsing a specialised pressure vessel chamber we show that elevations in intraluminal pressure increases gene expression of adhesion molecules and functional leukocyte adhesion to the endothelium in harvested vessels (P Ͻ 0.001). We also show that endothelial microparticles are shed from pressurised HUVECs (P Ͻ 0.05). Low shear stress (LSS: 1.6 dynes/cm 2 ) coupled with pressure (120mmHg) increased leukocyte adhesion compared to HSS (16 dyne/cm 2 ; 90 Ϯ 23 vs 24 Ϯ 9 leukocytes/fi eld respectively; n ϭ 5-6; P Ͻ 0.001). However, LSS on its own (with no pressure) had no infl uence (4 Ϯ 3 leukocytes/fi eld; n ϭ 4) suggesting that circumferential stretch plays a critical role. Electron microscopy images of pressurised vessels demonstrate caveolae disassembly, resulting in reduced caveolae number. To investigate the signalling pathways involved, we demonstrate that this acute infl ammatory response was reduced with the use of inhibitors of NADPH oxidase (P Ͻ 0.001) and mitochondrial permeability (P Ͻ 0.05). Increased reactive oxygen species production was also seen at 120mmHg in HUVECs perfused with the global ROS dye DCFH (60mmHg: 3 Ϯ 6 vs 120mmHg: 149 Ϯ 65 intensity units; n ϭ 5-7; P Ͻ 0.05).Results A total of 7130 participants were free of CKD at baseline, of which 6892(96.7%) had complete information on incident CKD events, retinal microvascular and systemic measurements. During a median follow-up of 4.3 years, 33 (0.5%) participants developed stage 5 CKD. After controlling for age, gender, ethnicity, systolic blood pressure, diabetes, smoking, total cholesterol and high-density-lipoprotein cholesterol, persons with retinopathy signs (hazards ratio [HR] 3.76; 95%CI 1.79-7.94] and retinal arteriolar narrowing (HR 1.53, 95%CI 1.06-2.19, per standard deviation decrease) had a higher risk of CKD. These associations were similar in persons with and without hypertension, and among the three ethnic groups.Conclusion Hypertensive retinopathy signs are associated with an increased risk of CKD independent of traditional risk factors.
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