ction of cardiomyocytes because AP-1 inhibition by JDP2 overexpression attenuated contractile responses induced by -adrenoceptor stimulation. Therefore, to prevent adverse remodelling, inhibition of SMAD signalling seems to be the better choice than inhibition of AP-1, because this would negatively influence the contractile function of the heart. Overview about TGF influence on components of cardiac remodelling in left ventricular systolic heart failure. TGF has been shown to promote the transition from cardiac hypertrophy to apoptosis and to regulate mitochondrial signalling molecules, miRNA expression and contractile function and fibrosis. All these processes are involved in heart failure progression. Modulation of -adrenoceptor responses in the presence of TGF During heart failure, progressive desensitization of adrenoceptors occurs. -adrenoceptors are members of the GPCR superfamily whose stimulation results in activation of PKA via AC and cAMP which regulate different intracellu, lar, sarcolemmal and myofibrillar substrates. Thus, cAMP exerts the cellular effects on cardiac contractile function induced by activation of -adrenoceptors. However, stimulation of -adrenoceptors also results in agonist-dependent desensitization of these receptors, a phenomenon found during the development of heart failure. This process is Salianic acid A site mediated by the receptor adapter protein -arrestin that binds to -adrenoceptors. This binding either results in direct British Journal of Pharmacology 173 314 5 necroptosis induced by TNF stimulation and prevents adverse cardiac remodelling. Necroptosis is a form of cell death, which combines features of necrotic and apoptotic cell death, it is a death receptor-mediated process which is executed via receptor activating protein complexes. During TNF stimulation, TAK1 BJP J Heger et al. Influence of TGF-SMAD and TGF-TAK1 signalling on adrenoceptor-mediated pathways in LV heart failure progression. Adrenoceptors stimulate the expression of genes promoting hypertrophic growth via the transcription factor AP-1. Under simultaneous presence of SMAD4, the prohypertrophic response to adrenoceptor stimulation is shifted to a pro-apoptotic gene transcription via AP-1/SMAD complexes. Also, under TGF stimulation of cardiomyocytes, AP-1 and SMADs mediate apoptosis. In addition to these effects on cardiomyocytes, activation of the TGF/SMAD pathway or induction of SMADs via -arrestins induces the transcription of fibrotic genes. In contrast to the SMAD pathway, TAK1 activation stimulates hypertrophic growth while inhibiting cardiac necroptosis and apoptosis by interacting with RIP1. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19822663 Strong -adrenoceptor activation results in -adrenoceptor desensitization via -adrenoceptor /-arrestin complexes. This process can be inhibited by TGF. Depicted in red are switch molecules that can modulate the response of the cell to receptor stimulation and thereby influence the outcome 
of this stimulation on the remodelling process. inhibition of -adrenoceptors, known as functional desensitization, or in internalization of -adrenoceptors that reduces their density. Studies in -arrestin1 knock-out mice demonstrated a major role for -arrestin1 in cardiac dysfunction, because contractile responses to -adrenoceptor stimulation were enhanced in these knock-out animals. Furthermore, knock-down of arrestin1 prevented adverse cardiac remodelling after myocardial infarction by inhibiting apoptosis and preserving cardiac function. Interestingly, an increase in myoc