blasts, an important process in HC030031 biological activity adverse cardiac remodelling. The involvement of NLRP3 in cardiac fibrosis has been confirmed in an in vivo model of hypertension: angiotensin II infusion for 28 days resulted in TGF-mediated fibrosis in wild-type mice, but NLRP3-deficient mice were protected against this angiotensin II-induced fibrosis. NLRP3, therefore, is a newly identified mitochondrial signalling factor in TGF-induced cardiac remodelling that may promote the transition to heart failure as it facilitates ROS-mediated fibrosis. Increased ROS production induces the opening of the mitochondrial permeability transition pore that changes the permeability of the inner mitochondrial membrane, leading to mitophagy, fusion/fission events and biogenesis. Opening of the MPTP facilitates the release of pro-apoptotic factors from the mitochondria that stimulates the activation of caspases and finally leads to cell death. The addition of noradrenaline induced a concentration-dependent decrease in mitochondrial membrane potential that was associated with a switch from compensated hypertrophy to apoptosis, thereby indicating that MPTP opening is involved in British Journal of Pharmacology 173 314 7 BJP J Heger et al. The central role of mitochondria in LV heart failure can be modulated by TGF. Hypertrophy, fibrosis and apoptosis can be controlled by mitochondria via generation of ROS. NLRP3 is a newly identified molecule that enhances mitochondrial ROS production and that is controlled by TGF or angiotensin II. miR181c enhances ROS production via modulation of complex IV of the respiratory chain. TOM70, acting as a repressor of mitochondrial ROS production, is found to be reduced in heart failure. This reduction then provokes enhancement of ROS. Enhancement of mitochondrial uncoupling protein during stimulation of -adrenoceptors by noradrenaline and TGF-receptor activation results in reduced energy production and impaired contractile function. Opening of the MPTP plays a central role in the induction of apoptosis. Opening of this pore can be modulated by the accessory proteins VDAC and ANT1. Their expression is regulated by crystalline B, TGF, AngII, ROS and -adrenoceptors. Central molecules that modulate mitochondrial processes in heart failure are depicted in red. adverse remodelling. Inhibiting MPTP opening by overexpression of adenine nucleotide translocase 1 prevented TGF1-induced apoptosis in ventricular cardiomyocytes and improved cardiac function in rats with an activated reninangiotensin system. These findings highlight the contribution MPTP opening has to the adverse cardiac remodelling induced by TGF stimulation and indicate that ANT1 is a critical component at the inner mitochondria membrane for regulating MPTP opening. Besides modulation of MPTP opening, the B-cell lymphoma 2 family is a well-known gate keeper in mitochondriamediated apoptosis. TGF can stimulate or inhibit the expression of pro-apoptotic and anti-apoptotic Bcl-2 family members. After renal artery ligation, a model for angiotensinII/TGF-mediated cardiac hypertrophy, up-regulation of the pro-apoptotic family member Bax and the voltage-dependent anion channel-1 occurred. Together, they lead to permeabilization of the outer mitochondrial membrane, release of cytochrome c from the intermembrane space into PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19822652 the cytosol, formation of the apoptosome, activation of caspases and finally the induction of apoptosis. The small heat shock protein, crystalline B, is able to block the pro