Our laboratory has determined that the serine/threonine kinase Akt, a key downstream component of the IGF1/PI3K pathway, has a profound effect on cardiac function both in vivo and in vitro. Transgenic mice overexpressing an active mutant of Akt exhibited increased myocardial inotropy in vivo and in vitro and increased lusotropy in vitro, along with the known role of Akt in physiologic hypertrophy. Our recent data show that Akt induces phosphorylation of phospholamban (PLB), a critical regulator of SERCA2a, the pump responsible for Ca2+uptake from the sarcoplasmic reticulum (SR) at Thr-17, a residue phosphorylated by Ca2+/Calmodulin-dependent kinase 2 (CAMK2). Thus, our working hypothesis is that Akt improves cardiac function by regulating critical SR components. Preliminary data further show also that stimulation of cardiomyocytes with IGF-1, which activates Akt, induces CAMK-dependent PLB phosphorylation. Moreover, they show that Akt overexpression improves cardiac function in the MLP knockout mouse model of heart failure.
The aims of this research project are therefore: 1) To characterize the role of CAMK2 in mediating the effects of Akt on inotropism and lustropism through biochemical and functional experiments on cardiac myocytes and isolated SR vesicles. The relevance of AKT-dependent CAMK activation at the organ level in vivo will be addressed in inducible and tissue-specific knockout mice of CAMK 2 and Akt signaling pathways. 2) To establish how Akt improves cardiac function in the MLP knockout mouse, a model of hypotrophic dilated cardiomyopathy. MLP and E40K Akt mice have been crossed; in vivo myocardial gene transfer will also be performed. Preliminary data show that the Akt-induced improvements of cardiac function in MLP mice is dependent on activation of protein synthesis and increased SERCA2a protein levels. Our studies therefore aim to define the mechanism of Akt modulation of cardiac contractility and whether manipulation of the Akt pathway can be used to improve cardiac function in heart failure. ? ? ?
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