Plasma Molecular Signatures in Hypertensive Patients With Renin-Angiotensin System Suppression: New Predictors of Renal Damage and De Novo Albuminuria Indicators

Albuminuria is a risk factor strongly associated with cardiovascular disease, the first cause of death in the general population. It is well established that renin-angiotensin system suppressors prevent the development of new-onset albuminuria in naïf hypertensive patients and diminish its excretion, but we cannot forget the percentage of hypertensive patients who develop de novo albuminuria. Here, we applied multiple proteomic strategy with the purpose to elucidate specific molecular pathways involved in the pathogenesis and provide predictors and chronic organ damage indicators. Briefly, 1143 patients were followed up for a minimum period of 3 years. One hundred and twenty-nine hypertensive patients chronically renin-angiotensin system suppressed were recruited, classified in 3 different groups depending on their albuminuria levels (normoalbuminuria, de novo albuminuria, and sustained albuminuria), and investigated by multiple proteomic strategies. Our strategy allowed us to perform one of the deepest plasma proteomic analysis to date, which has shown 2 proteomic signatures: (1) with predictive value of de novo albuminuria and (2) sustained albuminuria indicator proteins. These proteins are involved in inflammation, immune as well as in the proteasome activation occurring in situations of endoplasmic reticulum stress. Furthermore, these results open the possibility of a future strategy based on anti-immune therapy to treat hypertension which could help to prevent the development of albuminuria and, hence, the progression of kidney damage.N

The Influence of Coronary Artery Disease in the Development of Aortic Stenosis and the Importance of the Albumin Redox State.

Calcific aortic valve and coronary artery diseases are related cardiovascular pathologies in which common processes lead to the calcification of the corresponding affected tissue. Among the mechanisms involved in calcification, the oxidative stress that drives the oxidation of sulfur-containing amino acids such ascysteines is of particular interest. However, there are important differences between calcific aortic valve disease and coronary artery disease, particularly in terms of the reactive oxygen substances and enzymes involved. To evaluate what effect coronary artery disease has on aortic valves, we analyzed valve tissue from patients with severe calcific aortic stenosis with and without coronary artery disease. Proteins and peptides with oxidized cysteines sites were quantified, leading to the identification of 16 proteins with different levels of expression between the two conditions studied, as well as differences in the redox state of the tissue. We also identified two specific sites of cysteine oxidation in albumin that have not been described previously. These results provide evidence that coronary artery disease affects valve calcification, modifying the molecular profile of aortic valve tissue. In addition, the redox proteome is also altered when these conditions coincide, notably affecting human serum albumin.This research was funded by the Junta de Comunidades de Castilla-La Mancha (JCCM, co-funded by the European Social Fund, SBPLY/19/180501/000226), the Instituto de Salud Carlos III through the project PI18/00995, PI21/00384 (co-funded by European Regional Development Fund/European Social Fund—“Investing in your future”) Sociedad Española de Cardiología, 2020, Grant PRB3 (IPT17/0019—ISCIII-SGEFI/ERDF), Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00) and “la Caixa” Banking Foundation (project code HR17-00247). These results are aligned with the Spanish initiative on the Human Proteome Project (SpHPP).S

Potential role of new molecular plasma signatures on cardiovascular risk stratification in asymptomatic individuals

The evaluation of cardiovascular (CV) risk is based on equations derived from epidemiological data in individuals beyond the limits of middle age such as the Framingham and SCORE risk assessments. Lifetime Risk calculator (QRisk®), estimates CV risk throughout a subjects' lifetime, allowing those. A more aggressive and earlier intervention to be identified and offered protection from the consequences of CV and renal disease. The search for molecular profiles in young people that allow a correct stratification of CV risk would be of great interest to adopt preventive therapeutic measures in individuals at high CV risk. To improve the selection of subjects susceptible to intervention with aged between 30-50 years, we have employed a multiple proteomic strategy to search for new markers of early CV disease or reported CV events and to evaluate their relationship with Lifetime Risk. Blood samples from 71 patients were classified into 3 groups according to their CV risk (healthy, with CV risk factors and with a previously reported CV event subjects) and they were analyzed using a high through quantitative proteomics approach. This strategy allowed three different proteomic signatures to be defined, two of which were related to CV stratification and the third one involved markers of organ damage.This work was supported by grants from the Instituto de Salud Carlos III (PI070537, IF08/3667-1, PI11-02239, PI 14/01917, PI11/01401, PI11/02432, PI13/01873, PI13/01746, PI13/01581, PI14/01650, PI14/01841), PT13/0001/0013, PIE13/00051, PIE13/00045, CP09/00229, CP15/00129, IDC Salud (3371/002), the MutuaMadrileña Foundation, the SENEFRO Foundation and FONDOS FEDER (RD06/0014/1015, RD12/0042/0071). Sociedad Española de cardiología para la Investigación Básica 2017. Grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF. These results are in line with the Spanish initiative on the Human Proteome Project.S

Oxidative Stress in Cardiovascular Diseases

Cardiovascular diseases encompass a range of pathologies that affect the heart or blood vessels. Oxidative stress is an important factor that contributes to the development of these pathologies. Adverse effects due to oxidative stress manifest when there is an imbalance between the production and elimination of reactive oxygen species (ROS), or when physiological mechanisms of repair for oxidative injury are overburdened. This chapter focuses on ROS accumulation and antioxidant system deficiencies in the context of their influence on cardiovascular disease. We also discuss the importance of high throughput approaches, such as proteomics, with regard to their role in advancing the field of precision medicine for cardiovascular diseases, while keeping in mind the ultimate goal of improving patient care and quality of life

Contribution of proteomics to the management of vascular disorders

AbstractVascular disorders, and in particular atherothrombosis, are currently a leading cause of morbidity and mortality in Western societies. Proteomics research into these disorders has helped improving our knowledge of the underlying mechanisms involved in the development of atherothrombosis, as well as providing novel biomarkers to diagnose and for the prognosis of this disease. However, the application of these advances into clinical use has not followed this trend. In this review we explore the potential of Proteomics and Metabolomics for the management of vascular disorders, paying special attention to atherothrombosis and aiming to guide the reader from the experimental design of proteomic analysis through the initial discovery phase to the clinical implementation of biomarkers or therapeutic targets (Fig. 1), providing state-of-the-art proteomic studies to exemplify the concepts addressed

Potential blood biomarkers for stroke

Stroke is one of the most common causes of death worldwide and a major cause of acquired disability in adults. Despite advances in research during the last decade, prevention and treatment strategies still suffer from significant limitations, and therefore new theoretical and technical approaches are required. Technological advances in the proteomic and metabolomic areas, during recent years, have permitted a more effective search for novel biomarkers and therapeutic targets that may allow for effective risk stratification and early diagnosis with subsequent rapid treatment. This review provides a comprehensive overview of the latest candidate proteins and metabolites proposed as new potential biomarkers in stroke.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

Comprehensive Proteomic Profiling of Pressure Ulcers in Patients with Spinal Cord Injury Identifies a Specific Protein Pattern of Pathology

Objective: Severe pressure ulcers (PUs) do not respond to conservative wound therapy and need surgical repair. To better understand the pathogenesis and to advance on new therapeutic options, we focused on the proteomic analysis of PU, which offers substantial opportunities to identify significant changes in protein abundance during the course of PU formation in an unbiased manner. Approach: To better define the protein pattern of this pathology, we performed a proteomic approach in which we compare severe PU tissue from spinal cord injury (SCI) patients with control tissue from the same patients. Results: We found 76 proteins with difference in abundance. Of these, 10 proteins were verified as proteins that define the pathology: antithrombin-III, alpha-1-antitrypsin, kininogen-1, alpha-2-macroglobulin, fibronectin, apolipoprotein A-I, collagen alpha-1 (XII) chain, haptoglobin, apolipoprotein B-100, and complement factor B. Innovation: This is the first study to analyze differential abundance protein of PU tissue from SCI patients using high-throughput protein identification and quantification by tandem mass tags followed by liquid chromatography tandem mass spectrometry. Conclusion: Differential abundance proteins are mainly involved in tissue regeneration. These proteins might be considered as future therapeutic options to enhance the physiological response and permit cellular repair of damaged tissue.This work was supported by grants from the Instituto de Salud Carlos III (PI14/01917, PI18/00995, PT13/0001/0013) for Funding: ISCIII (‘‘PI14/01917, PI18/00995, PT13/0001/0013)’’, co-funded by ERDF/ESF, ‘‘Investing in your future’’. Redes Tema ticas de Investigacion Cooperativa (FONDOS FEDER, RD12/0042/0071). Sociedad Espanola de Cardiologıa para la Investigacion Basica 2017. Grant PRB3 (IPT17/0019—ISCIII-SGEFI/ERDF). These results are aligned with the Spanish initiative on the Human Proteome Project (SpHPP).S

Inside human aortic stenosis: a proteomic analysis of plasma

This work was supported by grants from the Instituto de Salud Carlos III (FIS PI070537, CP09/00229), Fondo de Investigación Sanitaria de Castilla la Mancha (FISCAM, PI2008/28 and PI2008/08) and Redes Temáticas de Investigación Cooperativa (FONDOS FEDER, RD06/0014/1015), CNIC.Valvular aortic stenosis (AS) produces a slowly progressive obstruction in left ventricular outflow track. For this reason, aortic valve replacement is warranted when the valvular stenosis is hemodinamically significant, becoming the most common worldwide cause of aortic valve surgery. Recent epidemiologic studies have revealed an association between degenerative AS and cardiovascular risk factors for atherosclerosis, althought reducing the exposure to such factors and statin therapies both fail to delay or reverse the pathology. Hence, a deeper understanding of the pathophysiology of this disease is required to identify appropriate preventive measures. A proteomic analysis of plasma will permit to know and identify the changes in protein expression induced by AS in this tissue. Using two-dimensional difference gel electrophoresis (2D-DIGE) followed by mass spectrometry (MS), we compared the crude (not pre-fractioned) and pre-fractioned plasma from AS patients and control subjects. We sought to identify plasma proteins whose expression is modified in AS. In addition we investigated if crude plasma presented some alterations in the more abundant proteins since to date, has never been studied before. We also further investigated the link between this disease and atherosclerosis with a view to identifying new potential markers and therapeutic targets.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu