Telomerase Deficiency Predisposes to Heart Failure and Ischemia-Reperfusion Injury

Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency.Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress.Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT−/− rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT−/− compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n = 6 in each group; p < 0.05) in the TERT−/−. Interestingly, infarct size was less in TERT−/− rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT−/− compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT−/− compared to the WT.Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease

Characterization of the inflammatory cell infiltrate and expression of costimulatory molecules in chronic echinococcus granulosus infection of the human liver

Background: The local immune responses to chronic echinococcal infections in various organs are largely unknown. Since the liver is the most frequently involved organ in such infections in human we aimed to characterize the inflammatory as well as immune cell infiltrate around hydatid cysts in the liver and compared to common inflammatory processes of the liver. Method: Surgical samples from the liver of 21 cystic echinococcosis (CE) patients were studied and the distribution of different types of inflammatory and immune cells were determined by immunohistochemistry. Furthermore, expression levels of costimulatory CTLA4, CD28, CD80 and CD86 molecules were measured at RNA level by PCR. Liver biopsy samples from patients with steatohepatitis (SH, n = 11) and chronic hepatitis (CH, n = 11) were used as non-inflammatory and chronic inflammatory controls, respectively. The composition and density of the inflammatory and immune cell infiltrates have been compared by using morphometry. Results: CD3+ T cells predominated the inflammatory infiltrate in all pathological processes, while in CE samples CD20+ B cells, in CH samples CD68+ macrophages were also frequent. Both myeloperoxidase (MPO) + leukocytes and CD68+ macrophages were found to be significantly decreased in CE as compared to either SH or CH samples. Concerning T cell subtypes, only CD8+ T cells were found to be significantly decreased in SH samples. CD1a + dendritic cells were almost completely missing from CE biopsies unlike in any other sample types. There were no differences detected in the mRNA expression of costimulatory molecules except decreased expression of CD28 in CE samples. Conclusion: In the hydatid lesions of the liver of chronic echinococcal infections T cell-mediated immunity seems to be impaired as compared to other types of chronic inflammatory processes, suggesting an immunosuppressive role for Echinococcus granulosus, which deserve further attentions

AlN films deposited by dc magnetron sputtering and high power impulse magnetron sputtering for SAW applications

International audienceIn this work, aluminium nitride (AlN) films were deposited on silicon substrates buffered by an epitaxial AlN thin film for surface acoustic wave (SAW) applications. The films were deposited by dc magnetron sputtering (dcMS) and high power impulse magnetron sputtering (HiPIMS) deposition techniques. The structural properties of AlN films were investigated using x-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy and atomic force microscopy. In both cases of films deposited by dcMS and HiPIMS, the XRD results showed that the obtained films are oriented, with full width at half maximum rocking curves of around 1 degrees. Raman spectroscopy revealed higher residual stress relaxation in the AlN epilayers grown by HiPIMS compared to AlN grown by dcMS, highlighted by a blue shift in the E2(high) Raman mode. The SAW measurements indicated an insertion loss of AlN-SAW devices of about 53 and 35 dB for the AlN films deposited by dcMS and HiPIMS respectively. The relation between the structural properties of AlN and the characteristics of AlN-SAW devices were correlated and discussed

Achieving high thermal conductivity from AlN films deposited by high-power impulse magnetron sputtering

International audienceWe report on thermal conductivity measurements of aluminum nitride (AlN) films using the fast pulsed photo-thermal technique. The films were deposited by high-power impulse magnetron sputtering with different thicknesses ranging from 1000 to 8000 nm on (1 0 0) oriented silicon substrates. The films were characterized by x-ray diffraction (XRD), Raman spectroscopy, profilometry, scanning electron microscopy and atomic force microscopy. The XRD measurements showed that AlN films were textured along the (0 0 2) direction. Moreover, x-ray rocking curve measurements indicated that the crystalline quality of AlN was improved with the increase in film thickness. The thermal conductivities of the samples were found to rapidly increase when the film thickness increased up to 3300 nm and then showed a tendency to remain constant. A thermal boundary resistance as low as 8 × 10−9 W−1 K m2 and a thermal conductivity as high as 250 ± 50 W K−1 m−1 were obtained for the AlN films, at room temperature. This high thermal conductivity value is close to that of an AlN single crystal and highlights the potential of these films as a dielectric material for thermal management

Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process

Brain and gonadal aromatases as molecular and biochemical targets of endocrine disrupters in a model species, the zebrafish (Danio rerio).

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