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Characterization of Endothelial Cells dysfunction associated to Acute Myocardial Infarction: modulation of metabolic pathways as a new therapeutic approach

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Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular

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[eng] The endothelium plays a pivotal role in the development of cardiovascular disease (CVD) and emerging evidence indicates that pathological blood vessel responses and endothelial dysfunction are associated with metabolic alterations in endothelial cells (ECs).
This project aims at performing a complete characterization of the metabolic profiles of an endothelial pathological Acute Myocardial Infarction (AMI) model of 8 patients. The results discussed throughout this thesis are part of this attempt, and brought to the identification of the insights and causes of the AMI pathology, as a consequence of the metabolic alterations related to the endothelium dysfunction which occurs in patients. 
Due to patients variability, finding a single and clear mechanism among all is quite hard to grasp. However, we have been able to find some metabolic feature to be exploited as possible biomarker for the identification of this CVD. Patients cells presented a low proliferation rate and unveiled a dependence to mitochondrial metabolism, which results in an increased ROS-oxidative stress. Consequently, these cells express increased level of glutathione that supplies the antioxidant defense and prevent ROS (Reactive oxygen species) accumulation. Glutamine seems to play a key role in this AMI model; first of all it is necessary for these cells to display a proper mitochondrial function and in addition, it is required for the synthesis of glutathione as antioxidant against the high level of ROS detected. Additionally, finding a higher content of glutaminase C (GAC) in patients, has opened the possibility that these cells rely more on glutaminase reaction for their survival, and this dependence gathered with the augmented need to neutralize the acidic pH , which results from the increased lactate production, by the ammonia molecules released from glutamine metabolism. This findings point that in AMI model is occurring a metabolic adaptation similar to the Warburg effect, usually described in cancer cells.
In the frame of finding the same origin among different pathologies ,in the second part of this work we focused on the crosstalk between dysfunctional endothelium and tumor microenvironment. Moreover, nowadays there is an increasing interest in supporting the existence of a link between cardiovascular pathologies and cancer. 
One of the wide possibilities which lies these two lethal morbidities is a an alteration of the DNA repair system, crucial for the recovery of the healthy cells against the diseased ones, when a pathological event takes place. Through this study we found that: alternative splicing governs cell‐type regulated expression of variant forms of mRNAs and their encoded proteins that exert differential function. So, employing cancer cell model in which distinct tumor cell subpopulations display differentiated epithelial or mesenchymal phenotype, we have identified alternatively spliced mRNAs with potential impact on the self‐renewal capacities of these cell subpopulations. More in details, among all the genetic characters which can be involved in this process, we provide evidences that RAP80 (UIMC1), an adaptor protein with critical functions in homology-dependent DNA repair (HDR), is expressed as alternatively spliced isoforms in epithelial and mesenchymal cells, as a function of ESRP1/2 expression. More specifically, we have found that the ratio of expression of a full-length isoform to a short isoform of RAP80 is significantly higher in epithelial cells than mesenchymal cells in a prostate cancer cell model for EMT. RAP80 contains a region required for interaction with Abraxas , a core component of the BRCA1-A complex involved in DNA-damage repair. We propose that the ratio of full-length RAP80 to the short isoform lacking AIR is a new mechanism for the regulation of HDR mediated by BRCA1. A higher long/short RAP80 isoform ratio will favor, and lower ratios will counter, the recruitment of BRCA1-A complexes to DSBs.

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Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecular

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Characterization of Endothelial Cells dysfunction associated to Acute Myocardial Infarction: modulation of metabolic pathways as a new therapeutic approach