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Rubattu S.,University of Rome La Sapienza | Pagliaro B.,University of Rome La Sapienza | Pierelli G.,University of Rome La Sapienza | Santolamazza C.,University of Rome La Sapienza | And 3 more authors.
International Journal of Molecular Sciences | Year: 2015

Hypertension causes target organ damage (TOD) that involves vasculature, heart, brain and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS). Both in vitro and in vivo studies explored the role of mitochondrial oxidative stress as a mechanism involved in the pathogenesis of TOD in hypertension, especially focusing on atherosclerosis, heart disease, renal failure, cerebrovascular disease. Both dysfunction of mitochondrial proteins, such as uncoupling protein-2 (UCP2), superoxide dismutase (SOD) 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), calcium channels, and the interaction between mitochondria and other sources of ROS, such as NADPH oxidase, play an important role in the development of endothelial dysfunction, cardiac hypertrophy, renal and cerebral damage in hypertension. Commonly used anti-hypertensive drugs have shown protective effects against mitochondrial-dependent oxidative stress. Notably, few mitochondrial proteins can be considered therapeutic targets on their own. In fact, antioxidant therapies specifically targeted at mitochondria represent promising strategies to reduce mitochondrial dysfunction and related hypertensive TOD. In the present article, we discuss the role of mitochondrial oxidative stress as a contributing factor to hypertensive TOD development. We also provide an overview of mitochondria-based treatment strategies that may reveal useful to prevent TOD and reduce its progression. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Perino A.,University of Turin | Perino A.,Ecole Polytechnique Federale de Lausanne | Beretta M.,University of Turin | Beretta M.,Jena University Hospital | And 17 more authors.
Science Signaling | Year: 2014

Obesity is defined as an abnormal increase in white adipose tissue and has become a major medical burden worldwide. Signals from the brain control not only appetite but also energy expenditure, both of which contribute to body weight. We showed that genetic or pharmacological inhibition of two phosphatidylinositol 3-kinases (PI3Kβ and PI3Kγ) in mice reduced fat mass by promoting increased energy expenditure. This effect was accompanied by stimulation of lipolysis and the acquisition of the energy-burning characteristics of brown adipocytes by white adipocytes, a process referred to as "browning." The browning of the white adipocytes involved increased norepinephrine release from the sympathetic nervous system. We found that PI3Kβ and PI3Kγ together promoted a negative feedback loop downstream of the melanocortin 4 receptor in the central nervous system, which controls appetite and energy expenditure in the periphery. Analysis of mice with drug-induced sympathetic denervation suggested that these kinases controlled the sympathetic drive in the brain. Administration of inhibitors of both PI3Kβ and PI3Kγ to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3Kβ and PI3Kγ might represent a promising treatment for obesity. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved.


Ragione F.D.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Filosa S.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Scalabri F.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | D'Esposito M.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Frontiers in Genetics | Year: 2012

Since the discovery of MeCP2, its functions have attracted the interest of generations of molecular biologists. Its function as a transducer of DNA methylation, the major post-biosynthetic modification found throughout genomes, and its association with the neurodevelopmental disease Rett syndrome highlight its central role as a transcriptional regulator, and, at the same time, poses puzzling questions concerning its roles in physiology and pathology. The classical model of the MeCP2 function predicts its role in gene-specific repression through the binding of methylated DNA, via its interaction with the histone deacetylases and co-repressor complexes. This view has been questioned and, intriguing ly, new roles for MeCP2 as a splicing modulator and as a transcriptional activator have been proposed. Recent data have demonstrated that MeCP2 is extremely abundant in the neurons, where it reaches the level of histone H1; it is widely distributed, tracking the methylated CpGs, and regulates repetitive elements expression. The role of MeCP2 in maintaining the global chromatin structure is further sustained by its involvement in other biologically relevant phenomena, such as the Line-1 repetitive sequences retrotrans-position and the pericentromeric heterochromatin clustering during cellular differentiation. These new concepts renew the old view suggesting a role for DNA methylation in transcriptional noise reduction, pointing to a key role for MeCP2 in the modulation of the genome architecture. © 2012 Della Ragione, Filosa, Scalabrì and D'Esposito.


Bertulat B.,TU Darmstadt | de Bonis M.L.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Della Ragione F.,CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso | Lehmkuhl A.,TU Darmstadt | And 7 more authors.
PLoS ONE | Year: 2012

The X-linked Mecp2 is a known interpreter of epigenetic information and mutated in Rett syndrome, a complex neurological disease. MeCP2 recruits HDAC complexes to chromatin thereby modulating gene expression and, importantly regulates higher order heterochromatin structure. To address the effects of MeCP2 deficiency on heterochromatin organization during neural differentiation, we developed a versatile model for stem cell in vitro differentiation. Therefore, we modified murine Mecp2 deficient (Mecp2-/y) embryonic stem cells to generate cells exhibiting green fluorescent protein expression upon neural differentiation. Subsequently, we quantitatively analyzed heterochromatin organization during neural differentiation in wild type and in Mecp2 deficient cells. We found that MeCP2 protein levels increase significantly during neural differentiation and accumulate at constitutive heterochromatin. Statistical analysis of Mecp2 wild type neurons revealed a significant clustering of heterochromatin per nuclei with progressing differentiation. In contrast we found Mecp2 deficient neurons and astroglia cells to be significantly impaired in heterochromatin reorganization. Our results (i) introduce a new and manageable cellular model to study the molecular effects of Mecp2 deficiency, and (ii) support the view of MeCP2 as a central protein in heterochromatin architecture in maturating cells, possibly involved in stabilizing their differentiated state. © 2012 Bertulat et al.


Carnevale D.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | Carnevale D.,University of Rome La Sapienza | Mascio G.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | D'Andrea I.,Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed | And 9 more authors.
Hypertension | Year: 2012

Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease. © 2012 American Heart Association, Inc.

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