RESUMO
Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.
Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Biogênese de Organelas , Oxigênio/metabolismo , Animais , Hipóxia Celular , DNA Mitocondrial/genética , Regulação para Baixo/genética , Coração/embriologia , Insuficiência Cardíaca/genética , Ventrículos do Coração/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Oxirredução , Fosforilação Oxidativa , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Antiphospholipid syndrome (APS) is a condition in which the body produces antiphospholipid antibodies, resulting in arterial and venous thrombosis. Catastrophic antiphospholipid syndrome (CAPS) is a rare APS subtype characterized by acute thrombotic microangiography. Antiphospholipid antibodies cause thrombosis through activating and inhibiting properties. CAPS is caused by conditions or factors that trigger the production of antiphospholipid antibodies: genetics that increases the risk of antiphospholipid antibody-associated thrombosis, infection, surgery, medications, and malignancy. We present a unique case of CAPS in a 63-year-old male patient.