d apoptosis and hypertrophy. The effects were mediated by the upregulation of an autophagy controlling protein, the endosomal sorting complex required for transport III family protein purchase 518303-20-3 charged multivesicular body protein 2B. Thus, Zaglia et al. demonstrated the interplay between the ubiquitin proteasome system and autophagy and the importance of controlled degradation of proteins for the control of cardiac hypertrophy and apoptosis. UPS regulates important signalling pathways in the heart, including MAPK, JNK and calcineurin. Huang et al. suggested a proteasome-dependent mechanism for angiotensin IIinduced apoptosis in hearts that is accompanied by activation of insulin-like growth factor receptor II signalling. Heat shock transcription factor 1 acts as a repressor of IGF2R gene expression only if deacetylated by sirtuin 1. However, angiotensin II and subsequently JNK activation mediates sirtuin 1 degradation via the proteasome. This results in an increase in the acetylation of HSF1 that is then not able to bind to the IGF2R promoter So, sirtuin is a negative regulator of IGF2R, thereby protecting cardiomyocytes from apoptosis. In this context, it is remarkable that the IGF2R is required for the activation of latent TGF. In human umbilical-vein endothelial cells, 
the association of IGF2R and the urokinase receptor converts plasminogen PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19821986 to active plasmin is essential for the activation of latent TGF, the release of TGF and induction of apoptosis. Whether this also holds true for cardiomyocytes remains to be evaluated, but we have already shown that angiotensin II induces the release of TGF and SMAD-dependent apoptosis in cardiomyocytes. Not only is the intracellular activity of TGF controlled by UPS but also the Influence of TGF on mitochondria, energy metabolism and heart failure Mitochondria are the power houses of the cell, generating A TP via oxidative phosphorylation. On average, 30% of the cardiomyocytes volume is filled with mitochondria. One side product of the major respiratory enzyme complexes is the generation of reactive oxygen species that modifies the redox potential of the cell and is essential for numerous signalling pathways. Mitochondrial dysfunction occurs under pathophysiological conditions and involves malfunction of complexes of oxidative phosphorylation, and an increase in ROS production that leads to cell death contributing to the development of heart failure. The enzymes of the respiratory chain seem to be the main site of ROS formation, but many other enzymes contribute to ROS production in failing hearts, including monoamine oxidases and the cytosolic adaptor protein p66Shc. Cellular stress signals lead to translocation of p66Shc into the mitochondrial intermembrane space, where it oxidizes cytochrome c and generates ROS. Factors that influence ROS production, therefore, critically determine the cell’s fate. A newly identified signalling molecule in the control of mitochondrial ROS production that is under the control of TGF signalling is nucleotide-binding domain and leucinerich repeat containing PYD-3, a pattern recognition receptor that is involved in the pathogenesis of chronic diseases and inflammation. NLRP3 is expressed in the heart, localized in mitochondria, and interacts with components of the redox system. Upon TGF stimulation of cardiac fibroblasts, NLRP3 increases mitochondrial ROS production, which supports SMAD2 phosphorylation and results in the differentiation of cardiac fibroblasts into myofibro
