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Studies on the Role of Intestinal Apolipoprotein A-I in HDL Physiology, Endotoxin Metabolism, and Systemic Inflammation
Get PDFSystemic inflammation is a major underlying risk factor for the development of cardiovascular disease and is often initiated or exacerbated by a Western diet (WD). It has been reported that elevated endotoxin and pro-inflammatory lipid species are hallmarks of diet-induced inflammation in mice. Apolipoprotein A-I (ApoA-I) is the primary constitutive and functional component of high-density lipoprotein (HDL), an anti-inflammatory lipoprotein with a critical role in the suppression of these endotoxic and lipotoxic effects. Approximately 70% and 30% of plasma HDL is of hepatic and enteric origin, respectively, but whether the tissue of origin is consequential in determining HDL functionality has not been fully evaluated. Accordingly, we are interested in the role of intestinal ApoA-I (IA1) in modulating enteric HDL (eHDL) to protect against systemic inflammatory insults such as WD, endotoxin, and dextran sulfate sodium (DSS). To address these unknowns, we have utilized a mouse model with a global double knockout (KO) of Low-Density Lipoprotein Receptor (LDLR) and ApoA-I (Ldlr-/- / ApoA-I-/- mice). We have also generated a novel inducible intestine-specific KO of ApoA-I in C57BL/6 mice on an LDLR-null background (Ldlr-/- / iApoA-I-/- mice) to further interrogate the functions of eHDL. To explore the effect of ApoA-I KO in the intestine of Ldlr-/- / ApoA-I-/- mice, we developed a novel fluorescence-activated cell sorting (FACS) protocol to isolate intestinal epithelial cells from mice fed chow or WD. Bulk RNA-Seq studies in these Ldlr-/- / ApoA-I-/- enterocytes revealed gene expression decreases in select apolipoproteins (Apoa4 and Apoc3) and increases in antimicrobial peptides (Reg3g, Defa4, and Muc4). Surprisingly, we have observed decreased endotoxin activity in the serum of Ldlr-/- / ApoA-I-/- mice fed WD. Interestingly, the decrease in endotoxin activity after WD was also observed in both serum and isolated HDL from Ldlr-/- / iApoA-I-/- mice. We have also observed decreased enzymatic activity of the anti-inflammatory and HDL-bound protein PON1 in WD-fed Ldlr-/- / iApoA-I-/- mice. Lastly, we characterized Ldlr-/- / iApoA-I-/- mice through analyses of the microbiome, HDL cholesterol efflux capacity, and lipidome of HDL and low-density lipoprotein (LDL). In contributing to the understanding of IA1 functionality, the studies we conducted can help elucidate the mechanism of action of apolipoprotein mimetic peptides, a class of anti-atherogenic and anti-cancer therapeutics that act on the intestine
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Anti-inflammatory and Antioxidant Properties of HDLs Are Impaired in Type 2 Diabetes
No full textOBJECTIVE-In mice, 4F, an apolipoprotein A-I mimetic peptide that restores HDL function, prevents diabetes-induced atherosclerosis. We sought to determine whether HDL function is impaired in type 2 diabetic (T2D) patients and whether 4F treatment improves HDL function in T2D patient plasma in vitro. RESEARCH DESIGN AND METHODS-HDL anti-inflammatory function was determined in 93 T2D patients and 31 control subjects as the ability of test HDLs to inhibit LDL-induced monocyte chemotactic activity in human aortic endothelial cell monolayers. The HDL antioxidant properties were measured using a cell-free assay that uses dichlorofluorescein diacetate. Oxidized fatty acids in HDLs were measured by liquid chromatography-tandem mass spectrometry. In subgroups of patients and control subjects, the HDL inflammatory index was repeated after incubation with L-4F. RESULTS-The HDL inflammatory index was 1.42 +/- 0.29 in T2D patients and 0.70 +/- 0.19 in control subjects (P < 0.001). The cell-free assay was impaired in T2D patients compared with control subjects (2.03 +/- 1.35 vs. 1.60 +/- 0.80, P < 0.05), and also HDL intrinsic oxidation (cell-free assay without LDL) was higher in T2D patients (1,708 +/- 739 vs. 1,233 +/- 601 relative fluorescence units, P < 0.001). All measured oxidized fatty acids were significantly higher in the HDLs of T2D patients. There was a significant correlation between the cell-free assay values and the content of oxidized fatty acids in HDL fractions. L-4F treatment restored the HDL inflammatory index in diabetic plasma samples (from 1.26 +/- 0.17 to 0.71 +/- 0.11, P < 0.001) and marginally affected it in healthy subjects (from 0.81 +/- 0.16 to 0.66 +/- 0.10, P < 0.05). CONCLUSIONS-In patients with T2D, the content of oxidized fatty acids is increased and the anti-inflammatory and antioxidant activities of HDLs are impaired. Diabetes 60:2617-2623, 201
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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Novel Distinct Roles for Intestinal/Macrophage COX-2 and Apolipoprotein Mimetic Peptides in the Development and Treatment of Inflammatory Bowel Diseases
Get PDFCyclooxygenase 2 (COX2) has been associated with the development of inflammatory bowel disease (IBD), but the nature of this association has remained unclear. I demonstrate that mice that lack COX2 lose tolerance to pathogen associated molecular patterns. Thus, challenge with dietary cholate—an environmental trigger that I show impairs intestinal barrier function—induces severe intestinal inflammation in COX2 knock-out mice. COX2 knock-out within the myeloid compartment is sufficient to drive disease upon cholate challenge, while also altering upon disease the balance between pro-inflammatory and inflammation resolving mediators towards a pro-inflammatory phenotype. ApoA-I mimetic peptides including 4F have been investigated as potential anti-inflammatory therapies. I show that 4F targets the small intestine, where it is transported into the intestinal lumen in a cholesterol-dependent manner. In turn, 4F can increase trans-intestinal cholesterol efflux, a secondary cholesterol efflux pathways whose modulation is of therapeutic import. 4F therapy abrogates disease in the myeloid COX2 knock-out and cholate model of IBD, while rescuing the elevated levels of pro-inflammatory mediators in macrophages, intestinal tissue, and plasma. 4F can directly clear lipid pro-inflammatory mediators from tissue and plasma, strongly suggesting a causative role for changes in the levels of these mediator in both the protective mechanism of 4F and the pathogenic mechanism of COX2-mediated IBD. Further investigation into the protective mechanism of 4F identified a novel trans-intestinal lipid transport clearance pathway for inflammatory mediators, which pathway may be involved in 4F’s protective mechanism. These findings are vivid examples of the synergy that can result from simultaneously investigating both pathogenic and protective mechanisms in genetic mouse models of disease
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Mechanisms Behind the Causal Role of Dietary Oxylipins of the Lipoxygenase Pathway in the Development of Pulmonary Arterial Hypertension
Get PDFHypertension, high blood pressure, is a common condition with more than three million cases in the United States per year. Pulmonary hypertension (PH), a chronic condition targeting the lungs, leading to vascular remodeling, right ventricle hypertrophy, and death in 50% of cases 5 years after diagnosis, is multi-factorial, not fully understood, and is without a permanent cure to this day. Utilizing multiple animal models involving xenobiotic injections, hypoxic conditions, growth factor receptor antagonists, and the combinations thereof have provided valuable insights into pathways and abnormalities associated with PH, however, the precise mechanisms remain unknown. In the last decade, it was discovered that a common feature of PH is the increase of oxidized lipids (especially the oxylipins of the lipoxygenase [LOX] pathway) in the plasma and lung tissues in not only human PAH patients but also in multiple animal models of PH. Animal studies demonstrated that apolipoprotein A-I (apoA-I) mimetic peptides ameliorated PH while lowering levels of oxylipins of the lipoxygenase pathway, including hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs). Taking this one step further, myself and our collaborators have developed a new animal model of PH in which feeding wild type C57BL6/J mice 5μg per mouse per day of 15-HETE resulted in increases in right ventricle systolic pressure (RVSP), Fulton index, vascular remodeling, lung weight, and plasma levels of HETEs and HODEs. In this thesis, I set out to utilize our new animal model to explore the mechanisms by which oxylipins of the lipoxygenase pathway (focusing on 15-HETE) cause PH and apoA-I mimetic peptides (specifically Tg6F) prevent the development of PH. My hypothesis is that 15-HETE initiates, and Tg6F mitigates, intestinal inflammation by modulating pro-inflammatory lipids and immune responses, which result in PH. I utilized cell culture (rat intestinal epithelial cells; IEC-6 cells, mouse T-cells; TK-1 cells, and mouse pulmonary arterial endothelial cells, PAECs), and animal models (C57BL6/J and 12/15 lipoxygenase KO mice) to test my hypothesis. I determined that 15-HETE diet (i) induces the accumulation of oxylipins in the intestine and plasma, (ii) activates pulmonary arterial endothelial cells (PAEC), and (iii) increases CD8 cell mediated PAEC apoptosis. I demonstrated that Tg6F treatment prevented all the above changes and prevented PH. Further, analyses of RNA-seq data from lung samples of PAH patients, lung samples of 15-HETE fed mice, and intestinal samples of 15-HETE fed mice, identified interferon induced protein 44 (IFI44) as the only gene that was significantly increased between all three groups. IFI44 increases in the intestine as early as one week into the 3 week 15-HETE PH protocol, preceding the increase in IFI44 observed in the lungs, and when IFI44 is blocked via intratracheal instillation of siRNA, it prevented the onset of PH in mice on the 15-HETE diet when compared with those administered scrambled siRNA, establishing IFI44 as a novel target for preventing PH. Finally, I determined that anti-inflammatory short chain fatty acids (SCFAs) play a role in the development of PH and identified oral butyrate as a potential therapy for PH. Luminal microbiota analysis from mice fed a 15-HETE diet revealed that bacterial species that participate in SCFA production were significantly reduced. Tg6F fed mice, interestingly, had increased SCFA producing bacterial species and fecal pellet levels of the SCFAs butyrate, propionate, and acetate compared to 15-HETE fed mice. Furthermore, supplementing 15-HETE fed mice with sodium butyrate in their drinking water increased the abundance of SCFA producing bacteria, decreased intestine and lung expression of IFI44, prevented the onset of PH, and reduced RVSP of mice fed 15-HETE diet for 2 weeks before adding sodium butyrate to their diet in the third, suggesting that oral butyrate is a potential therapy for both prevention and progression of PH. Combined, these experiments not only establish the role of oxylipins of the LOX pathway in the onset of PH, but also reveal mechanisms by which it causes it and multiple targets for future therapeutic applications
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Paraoxonase 2 (PON2) in Cardiovascular Disease (CVD): The Role of PON2 in Acute Myocardial Ischemia-Reperfusion Injury and Diet-Induced Obesity
Get PDFParaoxonase 2 (PON2) is a ubiquitously expressed antioxidant, anti-inflammatory protein localized in the inner mitochondrial membrane, where it protects against mitochondrial dysfunction and oxidative stress, among other protective properties. Human PON2 polymorphisms, particularly human PON2 Ser311Cys, has been implicated in the development of coronary artery disease, including myocardial infarction and ischemic stroke. Therefore, in this thesis, I explored the cardioprotective capacity of PON2 against myocardial infarction, specifically acute myocardial ischemia-reperfusion injury (IRI). My hypothesis is that PON2 protects against myocardial IRI in cardiomyocytes by modulating mitochondrial dysfunction and oxidative stress, particularly mitigating mitochondrial lipotoxicity (lipid peroxidation). I employed in vitro (rat ventricular cardiomyocyte cell line, H9c2 cells), ex vivo (cardiomyocytes derived from PON2-deficient mice hearts), and in vivo (PON2-deficient mice) models, subjecting them to cardiac IRI, to test my hypothesis. I determined that PON2 protects against myocardial IRI in cardiomyocytes by reducing mitochondrial dysfunction (stabilizing mitochondrial membrane potential and improving calcium retention capacity) and oxidative stress (reducing mitochondrial reactive oxygen species) via the reperfusion injury salvage kinase pathway (increasing phosphorylated glycogen synthase kinase-3β). Furthermore, there is an increase in mitochondrial lipid peroxidation in PON2-deficient mice subjected to myocardial IRI, with an increase in oxidized phosphatidylcholine species and eicosanoids (12, 15- hydroxyeicosatetraeonic acid), and a decrease in prostanoid production. These injuries are rescued by PON2 overexpression. Also, I observe an increase in cytoplasmic phospholipase A2 in the hearts of PON2-def mice subjected to myocardial IRI, serving as a potential mechanism by which PON2 modulates the increase in unesterified eicosanoid production. In order to further examine whether PON2 deficiency, exclusively in cardiomyocytes, is sufficient to induce increased myocardial IRI, I generated cardiomyocyte-specific PON2-KO mice. Lastly, I investigated the protective role of a novel drug, HSG4112, against cardiovascular risk factor, diet-induced obesity. I found that HSG4112 protects against diet-induced obesity by enhancing lactonase/arylesterase activity, reducing body weight and fat mass, and increasing lean (muscle) mass. Nevertheless, the protective effects of HSG4112 are significantly reduced in PON2-def mice, suggesting that PON2 is at least partly involved as a mode of action for HSG4112’s protective capacity
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ApoE-/- Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function
Get PDFObjective: We previously reported that Hemopexin (Hx), an acute phase protein and a heme scavenger, is significantly increased and associated with proinflammatory HDL under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating heme and ROS mediated oxidative damage to cells and tissues, the role of Hx in systemic oxidative stress, HDL function, macrophage function, and the development of atherosclerosis, is not known. Approach and Results: We generated Hx and apoE double knockout mice (HxE-/-) on a C57BL/6J background to determine the role of Hx in the development of atherosclerosis. HxE-/- mice had significantly more free heme, ROS, and proinflammatory and dysfunctional HDL in their circulation, when compared to control apoE-/- mice. Atherosclerotic plaque area (apoE-/- = 9.72 ± 2.5 x104 µm2and HxE-/- = 27.23 ± 3.6 x104 µm2) and macrophage infiltration (apoE-/- = 38.8 ± 5.8 x103 um2 µm2 and HxE-/- = 103.4 ± 17.8 x103 µm2) in the aortic sinus were significantly higher in the HxE-/- mice when compared to apoE-/- mice. Also, atherosclerotic lesions in the aortas were significantly higher in the HxE-/- mice when compared to apoE-/- mice. Analysis of polarization and phenotype revealed that macrophages from HxE-/- mice were more M1-like and proinflammatory. Ex vivo studies demonstrated that HxE-/- macrophage cholesterol efflux capacity was significantly reduced when compared to apoE-/- mice.Conclusion: We conclude that Hx plays a novel protective role in alleviating heme induced oxidative stress, improving inflammatory properties of HDL and macrophage function and inhibiting the development of atherosclerosis in apoE-/- mice
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