Вовлеченность генов матриксных металлопротеиназ в формирование артериальной гипертензии и ее осложнений (обзор)

Обобщены экспериментальные данные о генетических ассоциациях полиморфизмов генов матриксных металлопротеиназ (ММР) с развитием артериальной гипертензии и ее осложнений. Исследованы литературные данные об ассоциациях полиморфизмов генов ММР-1, ММР-2, ММР-3, ММР-7, ММР-8, ММР-9, ММР-12 с развитием АГ и ее осложнени

Integrated proteogenomic approach identifying a protein signature of COPD and a new splice variant of SORBS1

Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD

Early Onset Hypertension Is Associated With Hypertensive End-Organ Damage Already by MidLife

Early onset hypertension confers increased risk for cardiovascular mortality in the community. Whether early onset hypertension also promotes the development of target end-organ damage (TOD), even by midlife, has remained unknown. We studied 2680 middle-aged CARDIA (coronary artery risk development in young adults) Study participants (mean age 50±4 years, 57% women) who underwent up to 8 serial blood pressure measurements between 1985 and 2011 (age range at baseline 18-30 years) in addition to assessments of echocardiographic left ventricular hypertrophy, coronary calcification, albuminuria, and diastolic dysfunction in 2010 to 2011. Age of hypertension onset was defined as the age at first of 2 consecutively attended examinations with blood pressure ≥140/90 mm Hg or use of antihypertensive medication. Participants were divided in groups by hypertension onset age (<35 years, 35-44 years, ≥45 years, or no hypertension). While adjusting for TOD risk factors, including systolic blood pressure, we used logistic regression to calculate odds ratios for cases (participants with TOD) versus controls (participants without TOD) to examine the relation of hypertension onset age and hypertensive TOD. Compared with normotensive individuals, hypertension onset at age <35 years was related to odds ratios of 2.29 (95% CI, 1.36-3.86), 2.94 (95% CI, 1.57-5.49), 1.12 (95% CI, 0.55-2.29), and 2.06 (95% CI, 1.04-4.05) for left ventricular hypertrophy, coronary calcification, albuminuria, and diastolic dysfunction, respectively. In contrast, hypertension onset at age ≥45 years was not related to increased odds of TOD. Our findings emphasize the importance of assessing age of hypertension onset in hypertensive patients to identify high-risk individuals for preventing hypertensive complications

Longitudinal blood pressure patterns and cardiovascular disease risk

Observational and interventional studies have unequivocally demonstrated that "present", i.e. single-occasion, blood pressure is one of the key determinants of cardiovascular disease risk. Over the past two decades, however, numerous publications have suggested that longitudinal blood pressure data and assessment of long-term blood pressure exposure provide incremental prognostic value over present blood pressure. These studies have used several different indices to quantify the overall exposure to blood pressure, such as time-averaged blood pressure, cumulative blood pressure, blood pressure trajectory patterns, and age of hypertension onset. This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal blood pressure changes can be measured and used to improve cardiovascular disease risk prediction.KEY MESSAGES Numerous recent publications have examined the relation between cardiovascular disease and long-term blood pressure (BP) exposure, quantified using indices such as time-averaged BP, cumulative BP, BP trajectory patterns, and age of hypertension onset. This review summarises existing research on the association between these indices and hard cardiovascular outcomes, outlines the strengths and weaknesses of these indices, and provides an overview of how longitudinal BP changes can be measured and used to improve cardiovascular disease risk prediction. Although longitudinal BP indices seem to predict cardiovascular outcomes better than present BP, there are considerable differences in the clinical feasibility of these indices along with a limited number of prospective data.</p

Metabolic syndrome, the leptin gene and kidney disease in non-diabetic black South Africans

Includes abstract.Includes bibliographical references (leaves 226-256).Obesity is a worldwide problem and is a factor in the pathogenesis of the metabolic syndrome and kidney disease through the development of obesity-related hypertension and neurohormonal mechanisms that include the action of leptin. As there appear to be no focussed studies that have looked at the association of the LEP gene with kidney disease phenotypes or cardiovascular disease markers like hypertension, the metabolic syndrome and obesity, and especially so in native black Africans, this study sought to establish an association between the obesity gene (LEP) and kidney disease phenotypes (independent of diabetes and hypertension) in a homogenous black African population

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption

The Interaction of Obesity and Age and their effect on Adipose Tissue Metabolism in the Mouse

Numerous studies have investigated how bulk lipid metabolism is influenced in obesity and in particular how the composition of triglycerides found in the cytosol change with increased adipocyte expansion. However, in part reflecting the analytical challenge the composition of cell membranes, and in particular glycerophospholipids, an important membrane component, have been seldom investigated. Cell membrane components contribute to a variety of cellular processes including maintaining organelle functionality, providing an optimized environment for numerous proteins and providing important pools for metabolites, such as choline for one-carbon metabolism and S-adenosylmethionine for DNA methylation. Here, I have conducted a comprehensive lipidomic and transcriptomic study of white adipose tissue in mice that become obese either through genetic modification (ob/ob genotype), diet (high-fat diet) or a combination of the two across the life course. Specifically, I demonstrated that the changes in triglyceride metabolism that dominate the overall lipid composition of white adipose tissue were distinct from the compositional changes of glycerophospholipids. These latter lipids became more unsaturated to maintain the fluidity and normal function of the membrane in the initiation of obesity but then turned saturated after long-term administration of HFD and aging. This suggests that while triglycerides within the adipose tissue may be a relatively inert store of lipids, the compositional changes occur in cell membranes with more far-reaching functional consequences in both obesity and aging. The two-phase change of phospholipids can be correlated well with transcriptional and one-carbon metabolic changes within the adipocytes. The transcriptomic study demonstrated that the lipid metabolic pathways regulated by the peroxisome, AMPK, insulin and PPARγ signaling were activated in the initiation of obesity but inhibited in the adipose tissue of old ob/ob mice along with up-regulated inflammation pathways. The brown and white adipose tissue of PPARα-knock-out mice were also studied by lipidomic tools to get a deeper understanding of the effect of the peroxisome and PPAR system on adipose tissue and lipid metabolism during obesity. Most of the lipids were increased and became more saturated and shorter in adipose tissues of PPARα null mice, which is in good accordance with the results of the former animal study. In conclusion, my work using different rodent models and multi-omics techniques demonstrated a protective metabolic mechanism activated in the initiation but impaired at the end of the processes of obesity and aging, which could be an explanation of the similarity of obesity and aging in terms of high incidence of the metabolic syndrome and related diseases

The Role Of Nutrient Sensing Pathways In Delaying Ageing

Caloric restriction (CR) without malnutrition is a robust dietary intervention that extends lifespan and improves health in virtually every species studied. Recently, some of the mechanisms for the effects of CR on ageing have been elucidated, including several cellular master switches collectively called “nutrient sensing pathways”. CR is not sustainable in humans, therefore research has begun to focus on developing ad libitum-fed diets that maximise lifespan and healthspan. This thesis presents research on the effects of diets with differing ratios of macronutrients on nutrient sensing pathways, and their impact on ageing and age-related end points. This is achieved using the paradigm of the Geometric Framework (GF), an analytical tool used to disentangle the effects of various nutritional components such as macronutrient ratios and energy intakes on outcomes. Using the GF, a large-scale nutritional study is used to examine the aging process through genotypic and phenotypic changes in nutrient sensing pathways, and their relationship with parameters of health and lifespan. Taken together, the results presented here form a case that manipulation of the nutrient sensing pathways are a mechanism for the beneficial effects of dietary interventions on ageing and health. Further investigation of these growth pathways could help to develop guidelines for optimal nutritional intake, or form the basis for pharmacological interventions targeted at prolonging lifespan, healthspan, and promoting health in old age, without the use of long-term dietary manipulation. The algorithmic tools developed here, also have the potential to be applied to a wider array of experimental fields, supporting the overarching experimental model of comparing multi-dimensional inputs on responses, as opposed to the more commonly used control versus treatment model that is largely seen in scientific research