RESUMEN
Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM.
Asunto(s)
MicroARN Circulante , Enfermedad de la Arteria Coronaria , MicroARNs , Humanos , Masculino , MicroARNs/genética , MicroARNs/sangre , MicroARNs/metabolismo , Femenino , Persona de Mediana Edad , Anciano , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/sangre , MicroARN Circulante/sangre , MicroARN Circulante/genética , Diabetes Mellitus/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/sangre , Intervención Coronaria Percutánea/efectos adversos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Marcadores Genéticos , Células Endoteliales/metabolismo , Estudios de Casos y ControlesAsunto(s)
Modelos Animales de Enfermedad , Enfermedad de Fabry , Mitocondrias Cardíacas , Fenotipo , Animales , Enfermedad de Fabry/fisiopatología , Enfermedad de Fabry/genética , Enfermedad de Fabry/patología , Enfermedad de Fabry/metabolismo , Mitocondrias Cardíacas/patología , Mitocondrias Cardíacas/metabolismo , Ratones , Masculino , alfa-Galactosidasa/genética , alfa-Galactosidasa/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismoAsunto(s)
Cardiotoxicidad , Doxorrubicina , Macrófagos , MicroARNs , MicroARNs/metabolismo , MicroARNs/genética , Doxorrubicina/efectos adversos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Animales , Humanos , Antibióticos Antineoplásicos/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , RatonesAsunto(s)
Arginina , Cardiomiopatías Diabéticas , Suplementos Dietéticos , Mitocondrias Cardíacas , Humanos , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/tratamiento farmacológico , Arginina/administración & dosificación , Arginina/uso terapéutico , Animales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/patologíaAsunto(s)
Doxorrubicina , Macrófagos , Doxorrubicina/efectos adversos , Animales , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Antibióticos Antineoplásicos/efectos adversos , Cardiotoxicidad , Humanos , Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismoRESUMEN
Fabry disease (FD), also known as Anderson-Fabry disease, is a hereditary disorder of glycosphingolipid metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A enzyme. This causes a progressive accumulation of glycosphingolipids in tissues and organs which represents the main pathogenetic mechanism of FD. The disease is progressive and multisystemic and is characterized by early symptoms and late complications (renal, cardiac and neurological dysfunction). Fatigue and exercise intolerance are early common symptoms in FD patients but the specific causes are still to be defined. In this narrative review, we deal with the contribution of cardiac and pulmonary dysfunctions in determining fatigue and exercise intolerance in FD patients.
RESUMEN
Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.
RESUMEN
BACKGROUND: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest. OBJECTIVES: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment. METHODS: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox). RESULTS: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through ß-AR stimulation. CONCLUSIONS: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.
Asunto(s)
Catecolaminas , Doxorrubicina , Ratas , Ratones , Animales , Catecolaminas/metabolismo , Ratones Endogámicos C57BL , Doxorrubicina/efectos adversos , Apoptosis , Miocitos Cardíacos/metabolismo , Macrófagos , Estrés OxidativoRESUMEN
Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD). Here, we undertook the investigation of the energetic mechanisms related to FD-SM phenotype. A reduced tolerance to aerobic activity and lactate accumulation occurred in FD-mice and patients. Accordingly, in murine FD-SM we detected an increase in fast/glycolytic fibers, mirrored by glycolysis upregulation. In FD-patients, we confirmed a high glycolytic rate and the underutilization of lipids as fuel. In the quest for a tentative mechanism, we found HIF-1 upregulated in FD-mice and patients. This finding goes with miR-17 upregulation that is responsible for metabolic remodeling and HIF-1 accumulation. Accordingly, miR-17 antagomir inhibited HIF-1 accumulation, reverting the metabolic-remodeling in FD-cells. Our findings unveil a Warburg effect in FD, an anaerobic-glycolytic switch under normoxia induced by miR-17-mediated HIF-1 upregulation. Exercise-intolerance, blood-lactate increase, and the underlying miR-17/HIF-1 pathway may become useful therapeutic targets and diagnostic/monitoring tools in FD.
RESUMEN
Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for α-galactosidase A, inducing a progressive accumulation of globotriaosylceramide (GB3) and its metabolites in different organs and tissues. GB3 deposition does not fully explain the clinical manifestations of FD, and other pathogenetic mechanisms have been proposed, requiring the identification of new biomarkers for monitoring FD patients. Emerging evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial-related microRNAs (miRs) as potential biomarkers of mitochondrial involvement in FD. Indeed, we demonstate that miRs regulating different aspects of mitochondrial homeostasis including expression and assembly of respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are consistently dysregulated in FD patients. Our data unveil a novel noncoding RNA signature of FD patients, indicating mitochondrial-related miRs as new potential pathogenic players and biomarkers in FD. SIGNIFICANCE STATEMENT: This study demonstrates for the first time that a specific signature of circulating mitochondrial miRs (mitomiRs) is dysregulated in FD patients. MitomiRs regulating fundamental aspects of mitochondrial homeostasis and fitness, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, these new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.