Disease-related stresses trigger hypertrophic growth of the heart that confers markedly increased risk of failure and malignant rhythm disturbance. By contrast, growth of the heart in response to physiological demand is adaptive and not associated with adverse sequelae. Recently, we have shown that FoxO transcription factors play a key role in regulating cardiac myocyte growth. Conversely, the heart is capable of shrinking substantially under a variety of clinically relevant circumstances, such as mechanical support. Muscle atrophy is an active, energy-requiring process requiring activation of ubiquitin ligases. FoxO transcription governs this "atrogene" response. Thus, FoxO factors are situated at the nexus of multiple forms of cardiac plasticity. Here, we propose a comprehensive analysis of FoxO signaling in cardiac growth and remodeling. Our central hypothesis is that FoxO transcription factors are negative regulators of cardiac growth. We propose to define and manipulate the role of these molecules in 3 major forms of cardiac remodeling: 1) pathological hypertrophy stemming from hemodynamic stress;2) physiological hypertrophy of exercise;and 3) cardiac atrophy from ventricular unloading.
Aim 1 : To test the functional relevance of FoxO transcription factors during cardiac hypertrophy. Using gain-of-function and loss-of function strategies, we will define and manipulate the actions of FoxO in 2 major forms of cardiac growth, viz. pathological and physiological hypertrophy.
Aim 2 : To test the functional relevance of FoxO transcription factors during cardiac atrophy. Using a model of heterotopic cardiac transplantation, we will define and manipulate the actions of FoxO in the setting of ventricular unloading.
Aim 3 : To define and manipulate mechanisms whereby FoxO influences calcineurin and Akt activities, two key mediators of pathological and physiological hypertrophy, respectively. We have evidence that FoxO activation is a robust mechanism of suppressing calcineurin signaling, a major pathway leading to patho- logical cardiac hypertrophy. By contrast, signaling via the PI3K/Akt axis contributes to physiological heart growth, and we have data demonstrating that FoxO is capable of activating Akt. Here, we will decipher mechanisms whereby FoxO targets these major effectors of pathological (calcineurin) and physiological (Akt) cardiac hypertrophy.
Cardiovascular diseases are predicted to be the most common cause of mortality worldwide by the year 2020. Recent studies reveal that FoxO transcription factors are situated at the nexus of multiple forms of cardiac plasticity. By determining their role in pathological cardiac growth and atrophy, we will take steps that may lead to novel strategies to prevent heart failure in humans.
|Cao, Dian J; Lavandero, Sergio; Hill, Joseph A (2015) Parkin Gone Wild: Unbridled Ubiquitination. Circ Res 117:311-3|
|Daniels, James D; Hill, Joseph A (2015) Funny and late: targeting currents governing heart rate in atrial fibrillation. J Cardiovasc Electrophysiol 26:336-8|
|Wang, Zhao V; Hill, Joseph A (2015) Protein quality control and metabolism: bidirectional control in the heart. Cell Metab 21:215-26|
|Pedrozo, Zully; Criollo, Alfredo; Battiprolu, Pavan K et al. (2015) Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation 131:2131-42|
|Gillette, Thomas G; Hill, Joseph A (2015) Readers, writers, and erasers: chromatin as the whiteboard of heart disease. Circ Res 116:1245-53|
|Wang, Zhao V; Li, Dan L; Hill, Joseph A (2014) Heart failure and loss of metabolic control. J Cardiovasc Pharmacol 63:302-13|
|Bravo-Sagua, Roberto; Torrealba, Natalia; Paredes, Felipe et al. (2014) Organelle communication: signaling crossroads between homeostasis and disease. Int J Biochem Cell Biol 50:55-9|
|Parra, Valentina; Verdejo, Hugo E; Iglewski, Myriam et al. (2014) Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFÎºB-Opa-1 signaling pathway. Diabetes 63:75-88|
|Luo, Xiang; Hill, Joseph A (2014) CaÂ²âº in the cleft: fast and fluorescent. Circ Res 115:326-8|
|Morales, Cyndi R; Pedrozo, Zully; Lavandero, Sergio et al. (2014) Oxidative stress and autophagy in cardiovascular homeostasis. Antioxid Redox Signal 20:507-18|
Showing the most recent 10 out of 63 publications