Increased SERCA-2a connexin pPLB expression may occur as a result of lower myocardial UPS and have also been implicated as MCE Chemical 917879-39-1 downstream transcriptional targets of calcineurin. Thus, elevated connexin 43 and pPLB expression may represent an adaptive response by PI-treated hearts to improve calcium handling, which may improve cardiac function. Higher calcineurin activation also leads to increased dephosphorylation and translocation of NFAT3 to the nucleus for activation of downstream targets, e.g. PGC-1a and pro-hypertrophic genes. However, since the calcineurin-NFAT3 pathway did not result in cardiac hypertrophy in our model, we are of the opinion that longer-term activation may eventually result in a hypertrophic response. These findings, however, represent a model of altered cardiac physiology and suggest a potential association with PI-induced molecular alterations to key junction and ionic proteins that may precede the onset of contractile dysfunction. Moreover, the metabolic side-effects elicited by PI treatment in our model although at a relatively early stage �C may also affect heart function as a downstream MCE Company Danirixin target. Thus we do not imply that the protein expression alterations are directly associated with the altered contractility found in our model. Data linking these phenomena are scarce and therefore makes definitive conclusions difficult. Together these findings indicate that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction found in our experimental model in the longer term. However, further studies are required to confirm whether this is indeed the case. Since myocardial PGC-1a was upregulated, this implies that PIs exert initial effects at the mitochondrial level. PGC-1a is a welldescribed transcriptional regulator of mitochondrial biogenesis and we propose that higher expression levels may represent an early compensatory response to energetic stress. In agreement with this notion, NRF-1 and mtTFA expression remained unaltered while we previously identified no changes for myocardial ATP levels and AMPKa expression following 8 weeks of PI administration. It is likely that reduced UPS activity in PI-treated hearts may contribute to the increased PGC- 1a levels here observed. In support, others establis
