Short-term Akt activation in cardiac muscle cells improves contractile dysfunction in failing hearts.. Mus musculus

Akt is a serine/threonine protein kinase that is activated by a variety of growth factors or cytokines in a PI3-kinase dependent manner. Using a conditional transgenic system in which Akt signaling can be turned on or off in the adult heart, we have recently demonstrated that short-term Akt activation induces a ‘physiological’ form of cardiac hypertrophy with enhanced coronary angiogenesis and maintained contractility. Here we tested the hypothesis that induction of physiological hypertrophy by short-term Akt activation might improve contractile function in failing hearts. When Akt signaling was transiently activated in murine hearts with impaired contractility induced by pressure overload or adriamycin treatment, contractile dysfunction was attenuated in both cases. Importantly, improvement of contractility was observed before the development of cardiac hypertrophy, indicating that Akt improves contractile dysfunction independently of its growth-promoting effects. To gain mechanistic insights into Akt-mediated positive inotropic effects, transcriptional profiles in the heart were determined in a pressure overload-induced heart failure model. Biological network analysis of differentially expressed transcripts revealed significant alterations in the expression of genes associated with cell death, and these alterations were reversed by short-term Akt activation. Thus, short-term Akt activation improves contractile dysfunction in failing hearts. This beneficial effect of Akt on contractility is hypertrophy-independent and may be mediated in part by inhibition of cell death associated with heart failure. Keywords: transgenic mice, Akt1, cardiac hypertrophy after ascending aortic constriction and contractile dysfunction, DNA microarrays Overall design: Transcriptional profiles were determined in pressure overload-induced heart failure models. Mice were sacrificed at predetermined time points, and hearts were excised and snap-frozen in liquid nitrogen. RNA extraction, cDNA synthesis, biotinylated cRNA preparation, and hybridization of cRNA to microarrays (Affymetrix GeneChip Mouse Expression Set 430A and B) were performed. Data were obtained at three time points (before AAC, 4 weeks after AAC, and 6 weeks after AAC (2 weeks after Akt activation)), and three independent sets of hybridizations were performed at each time point.