Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression

Artículo de publicación ISIAltering chromatin structure through histone posttranslational modifications has emerged as a key driver of transcriptional responses in cells. Modulation of these transcriptional responses by pharmacological inhibition of class I histone deacetylases (HDACs), a group of chromatin remodeling enzymes, has been successful in blocking the growth of some cancer cell types. These inhibitors also attenuate the pathogenesis of pathological cardiac remodeling by blunting and even reversing pathological hypertrophy. The mechanistic target of rapamycin (mTOR) is a critical sensor and regulator of cell growth that, as part of mTOR complex 1 (mTORC1), drives changes in protein synthesis and metabolism in both pathological and physiological hypertrophy. We demonstrated through pharmacological and genetic methods that inhibition of class I HDACs suppressed pathological cardiac hypertrophy through inhibition of mTOR activity. Mice genetically silenced for HDAC1 and HDAC2 had a reduced hypertrophic response to thoracic aortic constriction (TAC) and showed reduced mTOR activity. We determined that the abundance of tuberous sclerosis complex 2 (TSC2), an mTOR inhibitor, was increased through a transcriptional mechanism in cardiomyocytes when class I HDACs were inhibited. In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC-dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine. These findings point to mTOR and TSC2-dependent control of mTOR as critical components of the mechanism by which HDAC inhibitors blunt pathological cardiac growth. These results also suggest a strategy to modulate mTOR activity and facilitate the translational exploitation of HDAC inhibitors in heart disease.NIH HL-120732 HL-100401 HL-126012 HL-097768 HL-072016 AHA (American Heart Association) 14SFRN20740000 CPRIT (Cancer Prevention and Research Institute of Texas) RP110486P3 RP110486-AC RP110486-P5 Leducq Foundation 11CVD04 CONICYT (Comision Nacional de Investigacion Cientifica y Tecnologica), Chile FONDAP 15130011 AHA 11POST7950051 14SDG1844000

D-JRA2.1 Simulator coupling and Smart Grid libraries

Work package JRA2 focuses on the development of advanced simulation-based methods to checkand validate smart grid scenarios, configurations and corresponding applications. The main aim isto employ offline simulation of scenarios where a combination of parallel processing, advanced optimization techniques, and design-of-experiments is used to master the system complexity. Secondary targets include the development of methods for HIL application as well as for the assessment of cyber-security concepts. This assessment will cover the following smart grid properties:system stability, system scalability, component interoperability, and information security. Eventuallyit is the goal to explore the operational limits and the sensitivity of these system properties towardssystem parameters.Intelligent Electrical Power Grid