Search

Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for alpha- galactosidase A (GAL) 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. Previous evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial related microRNA (miRNAs, miRs) as potential biomarkers of mitochondrial involvement in FD. We observed that miRNAs 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 non-coding RNA signature of FD patients, indicating mitochondrial related miRNAs (mitomiRs) as new potential pathogenic players and biomarkers in FD. Significance StatementWe demonstrate for the first time that a specific signature of circulating mitochondrial microRNAs (mitomiRs) are dysregulated in Fabry disease (FD). In our study, we observed that mitomiRs regulating fundamental aspects of mitochondrial homeostasis, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, our new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.

Our study aimed to explore the intercorrelations of brachial-ankle pulse wave velocity (baPWV), ankle-brachial index (ABI), ambulatory arterial stiffness index (AASI), 24-hour mean pulse pressure (24-h PP), and augmentation index (AIx, AIx@75, the AIx standardized to a heart rate of 75) and compare the effectiveness of these markers for predicting renal outcomes. A total of 117 patients with chronic kidney disease (CKD) who received noninvasive arterial stiffness examinations were enrolled. We used correlation analysis and linear regression to explore the correlations between these five arterial stiffness markers and the Cox proportional hazards model and receiver operator characteristic (ROC) curve to assess the associations of markers with kidney disease outcomes. The median (interquartile range) of age and eGFR were 61 (49-65) years and 50.5 (35.5-84.1) ml/min/1.73 m

ST-elevation myocardial infarction (STEMI) is one of the leading causes of death and hospitalization worldwide (1). Hyperglycemia (HG) has been shown to adversely affect STEMI clinical outcomes, leading to higher mortality and severe complications (1,2). The aim of our study was to investigate the impact of HG at hospital admission on the risk of restenosis after primary percutaneous coronary intervention (PCI) for STEMI, comparing normoglycemic subjects (NG group), patients without diabetes mellitus (DM) but with HG (HG-non-DM group), and patients with both HG and DM (HG-DM group). HG was defined by glycemia >140 mg/dL, according to the guidelines of the American Diabetes Association (3). We evaluated STEMI patients referred to the Division of Cardiology of “Antonio Cardarelli” Hospital from February 2008 to February 2016. Inclusion criteria were age >18 years and first STEMI. Exclusion criteria were left ventricular ejection fraction

Background. Ergogenic nutritional supplementation is sought by professional athletes for improving physical performance; nevertheless, scientific evidence to support the chronic use of L-Arginine among water polo players is missing. Methods. Seventeen male professional water polo players were randomly assigned to assume 5 grams per day of L-Arginine ( n = 9 ) or placebo ( n = 8 ) for 4 weeks. The players’ fitness level was assessed in the maximal speed swimming test. Ear lobe blood samples taken before and after the effort for serum lactate content were analyzed. A speed-to-lactate ratio was generated at the baseline and after 4 weeks of treatment. We also tested the effects of L-Arginine in vitro, measuring NO production, mitochondrial respiration, and gene expression in human fibroblasts. Results. L-Arginine did not modify BMI, muscle strength, and maximal speed at 200 meters after 4 weeks. However, L-Arginine ameliorated oxidative metabolism to exercise as suggested by the statistically significant lower lactate-to-speed ratio, which was not observed in placebo-treated controls. In vitro, L-Arginine induced the expression of a key regulator of mitochondrial biogenesis (PGC1α) and genes encoding for complex I and increased the production of nitric oxide and the maximal oxygen consumption rate. Conclusions. Chronic L-Arginine is safe and effective in ameliorating the oxidative metabolism of professional water polo players, through a mechanism of enhanced mitochondrial function.

The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.

Despite limited evidence on the association between physical activity (PA) and blood pressure (BP) in youth, experts recommend that adolescents engage regularly in moderate‐to‐vigorous PA. We examined the relationships between PA intensity and frequency and the likelihood of having high BP in a population‐based cohort of adolescents from Montréal, Canada. PA was self‐reported every 3 months from grade 7 to 11, and BP was measured at ages 12.8, 15.2, and 17.0 years on average. We analyzed data from 993 participants (mean [SD] age = 16.0 [1.0], 51.6% female) with BP data at ages 15.2 and/or 17.0 years, using pooled ordinal logistic regression. BP (normal/elevated/hypertensive range) was the outcome, and past‐year PA intensity and frequency were potential predictors. Eight percent of participants had elevated BP (120‐129/

Mitochondrial regulation of energy production, calcium homeostasis, and cell death are critical for cardiac function. Accordingly, the structural and functional abnormalities of these organelles (mitochondrial dysfunction) contribute to developing cardiovascular diseases and heart failure. Therefore the preservation of mitochondrial integrity is essential for cardiac cell survival. Mitochondrial function is regulated by several proteins, including GRK2 and β-arrestins which act in a GPCR independent manner to orchestrate intracellular signaling associated with key mitochondrial processes. It is now ascertained that GRK2 is able to recover mitochondrial function in response to insults. β-arrestins affect several intracellular signaling pathways within the cell which in turn are involved in the regulation of mitochondrial function, but a direct regulation of mitochondria needs further investigations. In this review, we discuss the recent acquisitions on the role of GRK2 and β-arrestins in the regulation of mitochondrial function.

G protein coupled receptor kinase type 2 (GRK2) plays an important role in the development and maintenance of cardiac hypertrophy and heart failure even if its exact role is still unknown. In this study, we assessed the effect of GRK2 on the regulation of cardiac hypertrophy. In H9C2 cells, GRK2 overexpression increased atrial natriuretic factor (ANF) activity and enhanced phenylephrine-induced ANF response, and this is associated with an increase of NFκB transcriptional activity. The kinase dead mutant and a synthetic inhibitor of GRK2 activity exerted the opposite effect, suggesting that GRK2 regulates hypertrophy through upregulation of NFκB activity in a phosphorylation-dependent manner. In two different in vivo models of left ventricle hypertrophy (LVH), the selective inhibition of GRK2 activity prevented hypertrophy and reduced NFκB transcription activity. Our results suggest a previously undisclosed role for GRK2 in the regulation of hypertrophic responses and propose GRK2 as potential therapeutic target for limiting LVH.

Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal β cells in a dose- and time-dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca2+) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca2+ uptake. Crucially, the reduced mitochondrial Ca2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug.

Introduction: Diabetes and cardiovascular disease are important health concerns in United States and worldwide. However, while the increased risk of cardiovascular disease and heart failure (HF) in diabetic patients has been established, the reciprocal relationship, i.e. the augmented risk of glucose intolerance and type 2 diabetes mellitus (TD2M) in patients with cardiovascular disorders, has been evidenced in the clinical scenario but the underlying mechanisms remain essentially unclear. Hypothesis: HF causes pancreatic beta cell dysfunction via endoplasmic reticulum (ER) stress and impairment of mitochondrial dynamics. Methods/Results: In this study we focused on the beta cell function in a murine model of post-ischemic HF, obtained via ligation of the coronary artery. The HF group exhibited glucose intolerance and impaired glucose-stimulated insulin release, with no major differences in islet architecture when comparing HF and SHAM. Islets isolated from HF mice displayed upregulation of common markers of ER stress, including BiP and spliced XBP. Ultrastructural analysis revealed significant mitochondrial dysmorphology (fragmented cristae, swelling, and outer membrane disruption) in HF beta cells. We also found significantly altered mitochondrial dynamics in ex vivo experiments in HF vs SHAM, including reduced glucose-stimulated and glutamine/leucine-stimulated ATP production, impaired oxygen consumption rate (measured at Seahorse), decreased mtDNA/nDNA, aconitase activity, and NADPH following glucose stimulation, alongside with augmented generation of reactive oxygen species. Strikingly, we demonstrate that during HF beta cells display decreased intracellular calcium stores, and mitochondria exhibit a significantly reduced glucose-stimulated uptake of calcium, known activator of three matrix dehydrogenases in the tricarboxylic acid (aka Krebs) cycle. Moreover, the expression of mitochondrial calcium uniporter (MCU) was decreased in HF islets. Conclusions: Taken together, our in vivo and ex vivo findings establish that HF induces beta cell failure, characterized by mitochondrial dysfunction, ER stress, and overall impaired fuel-stimulated insulin release.