Background and Purpose
Microsomal prostaglandin E synthase‐1 (mPGES‐1) is an inducible isomerase responsible for prostaglandin E2 production in inflammatory conditions. We evaluated the role of ...mPGES‐1 in the development and the metabolic and cardiovascular alterations of obesity.
Experimental Approach
mPGES‐1+/+ and mPGES‐1−/− mice were fed with normal or high fat diet (HFD, 60% fat). The glycaemic and lipid profile was evaluated by glucose and insulin tolerance tests and colorimetric assays. Vascular function, structure and mechanics were assessed by myography. Histological studies, q‐RT‐PCR, and western blot analyses were performed in adipose tissue depots and cardiovascular tissues. Gene expression in abdominal fat and perivascular adipose tissue (PVAT) from patients was correlated with vascular damage.
Key Results
Male mPGES‐1−/− mice fed with HFD were protected against body weight gain and showed reduced adiposity, better glucose tolerance and insulin sensitivity, lipid levels and less white adipose tissue and PVAT inflammation and fibrosis, compared with mPGES‐1+/+ mice. mPGES‐1 knockdown prevented cardiomyocyte hypertrophy, cardiac fibrosis, endothelial dysfunction, aortic insulin resistance, and vascular inflammation and remodelling, induced by HFD. Obesity‐induced weight gain and endothelial dysfunction of resistance arteries were ameliorated in female mPGES‐1−/− mice. In humans, we found a positive correlation between mPGES‐1 expression in abdominal fat and vascular remodelling, vessel stiffness, and systolic blood pressure. In human PVAT, there was a positive correlation between mPGES‐1 expression and inflammatory markers.
Conclusions and Implications
mPGES‐1 inhibition might be a novel therapeutic approach to the management of obesity and the associated cardiovascular and metabolic alterations.
Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the
(fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called ...fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.
Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (
) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A;
mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration.
The main canonical pathways highlighted in the transcriptomic analysis in aortas from
mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young
mice. In vitro experiments in
-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in
mice.
Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
During resolution of inflammation, specialized proresolving mediators (SPMs), including resolvins, are produced to restore tissue homeostasis. We hypothesized that there might be a dysregulation of ...SPMs pathways in pathological vascular remodeling and that resolvin D2 (RvD2) might prevent vascular remodeling and contractile and endothelial dysfunction in a model of obesity and hypertension. In aortic samples of patients with or without abdominal aortic aneurysms (AAA), we evaluated gene expression of enzymes involved in SPMs synthesis (ALOXs), SPMs receptors and pro-inflammatory genes. In an experimental model of aortic dilation induced by high fat diet (HFD, 60%, eighteen weeks) and angiotensin II (AngII) infusion (four weeks), we studied the effect of RvD2 administration in aorta and small mesenteric arteries structure and function and markers of inflammation. In human macrophages we evaluated the effects of AngII and RvD2 in macrophages function and SPMs profile. In patients, we found positive correlations between AAA and obesity, and between AAA and expression of ALOX15, RvD2 receptor GPR18, and pro-inflammatory genes. There was an inverse correlation between the expression of aortic ALOX15 and AAA growth rate. In the mice model, RvD2 partially prevented the HFD plus AngII-induced obesity and adipose tissue inflammation, hypertension, aortic and mesenteric arteries remodeling, hypercontratility and endothelial dysfunction, and the expression of vascular proinflammatory markers and cell apoptosis. In human macrophages, RvD2 prevented AngII-induced impaired efferocytosis and switched SPMs profile. RvD2 might represent a novel protective strategy in preventing vascular damage associated to hypertension and obesity likely through effects in vascular and immune cells.
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•GPR18 and ALOX15 are upregulated in human abdominal aortic aneurysms.•Human aortic ALOX15 negatively correlates with abdominal aortic aneurysms growth.•RvD2 partially prevents obesity and hypertension in obese hypertensive mice.•RvD2 partially prevents vascular remodeling in obese hypertensive mice.•RvD2 prevents endothelial dysfunction in obese hypertensive mice.
Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative ...regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF), and epinephrine in primary human vein (HV)-/artery (HA)-derived endothelial cells (ECs) and human dermal microvascular ECs (HMVEC-D). Vascular permeability was analyzed
in human ECs with forced Rcan1 expression using Transwell migration assays and
using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R). These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional
assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings,
models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of
-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans.
Cancer is the third cause of death in patients infected with human immunodeficiency virus (HIV) and lymphoma is the most common type.
To describe the clinical characteristics, histology, risk factors ...and prognosis of these patients, in a Chilean public hospital in Chile.
Records of 55 patients (45 males) aged between 23 and 67 years with lymphoma and HIV positive serology, diagnosed between 1992-2008, were reviewed.
Six patients (11%) had Hodgkin lymphoma (HL) and the rest, non-Hodgkin lymphoma (NHL). B-cell phenotype constituted 83.7% of NHL cases. The most common subtypes of all the lymphoma were diffuse large B cell lymphoma in 24 cases (43.6%), Burkitt lymphoma in 12 cases (21.8%), and plasmablastic lymphoma in 5 cases (9.1%). Thirty five patients (64%) underwent curative intended chemotherapy (CT) concomitantly with highly active antiretroviral therapy (HAART). Three year survival of the whole cohort was 27%. By multivariate analysis, the most important prognostic factors for long term survival, were complete responses to CT, (p < 0.01) and a low international prognostic index (IPI) score for NHL, (p = 0.01). HAART, histologic subtype and CD4 lymphocyte count at diagnosis, did not influence survival.
The most important prognostic factors for HIV patients with lymphoma, were achieving CR with CT and low IPI score. Prognosis remains poor, even with HAART therapy.
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