A Burgeiro1, A C Fonseca1, D Espinoza1, L Carvalho2, N Lourenço3, M Antunes4, E Carvalho5. 1. Center of Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. 2. Institute of Pathology, Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal. 3. Centre for Informatics and Systems of the University of Coimbra (CISUC), Department of Informatics Engineering, University of Coimbra, Portugal. 4. Cardiothoracic Surgery Unit at the Coimbra University Hospital Centre, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal. 5. Center of Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; The Portuguese Diabetes Association (APDP), 1250-203 Lisbon, Portugal; Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock 72202, AR, United States; Arkansas Children's Research Institute, Little Rock 72202, AR, United States. Electronic address: ecarvalh@cnc.uc.pt.
Abstract
BACKGROUND: Cardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death. UPR activation is an early event of diabetic cardiomyopathies and deregulated autophagy is associated with CVDs. RESULTS: An upregulation of UPR markers (glucose-regulated protein 78 KDa, glucose-regulated protein 94 KDa, inositol-requiring enzyme 1α, protein kinase RNA-like ER kinase and CCAAT/-enhancer-binding protein homologous protein (CHOP) gene) in EAT compared to subcutaneous adipose tissue (SAT), was observed as well as the UPR-related apoptosis marker caspase-4/procaspase-4 ratio but not in CHOP protein levels. Additionally, levels of ubiquitin and ubiquitinated proteins were decreased in EAT. Moreover, upregulation of autophagy markers (5' adenosine monophosphate-activated protein kinase, mechanistic target of rapamycin, Beclin 1, microtubule-associated protein light chain 3-II, lysosome-associated membrane protein 2, and PTEN-induced putative kinase 1) was observed, as well as an increase in the apoptotic Bim but not the ratio between Bim and the anti-apoptotic Bcl-2 in EAT. Diabetic patients show alterations in UPR activation markers but not in autophagy or apoptosis markers. CONCLUSION: UPR and autophagy are increased in EAT compared to SAT, opening doors to the identification of early biomarkers for cardiomyopathies and novel therapeutic targets.
BACKGROUND:Cardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death. UPR activation is an early event of diabetic cardiomyopathies and deregulated autophagy is associated with CVDs. RESULTS: An upregulation of UPR markers (glucose-regulated protein 78 KDa, glucose-regulated protein 94 KDa, inositol-requiring enzyme 1α, protein kinase RNA-like ER kinase and CCAAT/-enhancer-binding protein homologous protein (CHOP) gene) in EAT compared to subcutaneous adipose tissue (SAT), was observed as well as the UPR-related apoptosis marker caspase-4/procaspase-4 ratio but not in CHOP protein levels. Additionally, levels of ubiquitin and ubiquitinated proteins were decreased in EAT. Moreover, upregulation of autophagy markers (5' adenosine monophosphate-activated protein kinase, mechanistic target of rapamycin, Beclin 1, microtubule-associated protein light chain 3-II, lysosome-associated membrane protein 2, and PTEN-induced putative kinase 1) was observed, as well as an increase in the apoptotic Bim but not the ratio between Bim and the anti-apoptotic Bcl-2 in EAT. Diabeticpatients show alterations in UPR activation markers but not in autophagy or apoptosis markers. CONCLUSION: UPR and autophagy are increased in EAT compared to SAT, opening doors to the identification of early biomarkers for cardiomyopathies and novel therapeutic targets.