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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078797-03
Application #
7255458
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$292,988
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lim, Byung-Kwan; Peter, Angela K; Xiong, Dingding et al. (2013) Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy. J Clin Invest 123:5146-51
Sciarretta, Sebastiano; Zhai, Peiyong; Shao, Dan et al. (2012) Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 125:1134-46
Zhang, Denghong; Contu, Riccardo; Latronico, Michael V G et al. (2010) MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 120:2805-16
Catalucci, Daniele; Latronico, Michael V G; Ceci, Marcello et al. (2009) Akt increases sarcoplasmic reticulum Ca2+ cycling by direct phosphorylation of phospholamban at Thr17. J Biol Chem 284:28180-7
Elia, Leonardo; Contu, Riccardo; Quintavalle, Manuela et al. (2009) Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 120:2377-85
Catalucci, Daniele; Gallo, Paolo; Condorelli, Gianluigi (2009) MicroRNAs in cardiovascular biology and heart disease. Circ Cardiovasc Genet 2:402-8
Elia, L; Quintavalle, M; Zhang, J et al. (2009) The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 16:1590-8
Catalucci, Daniele; Zhang, Deng-Hong; DeSantiago, Jaime et al. (2009) Akt regulates L-type Ca2+ channel activity by modulating Cavalpha1 protein stability. J Cell Biol 184:923-33
Catalucci, Daniele; Latronico, Michael V G; Ellingsen, Oyvind et al. (2008) Physiological myocardial hypertrophy: how and why? Front Biosci 13:312-24
Kemi, Ole Johan; Ceci, Marcello; Condorelli, Gianluigi et al. (2008) Myocardial sarcoplasmic reticulum Ca2+ ATPase function is increased by aerobic interval training. Eur J Cardiovasc Prev Rehabil 15:145-8

Showing the most recent 10 out of 19 publications