verbatim): Primary degenerative changes in the failing heart include remodeling associated with loss of structural organization and cardiomyocyte apoptosis. Optimal treatment strategies must approach the long term goal of a molecular approach that promotes myocardial integrity and inhibits apoptosis to prevent ventricular dilation. Myocardial pathogenesis is inhibited by activation of Akt kinase, although the potential therapeutic effect of Akt activation has never been examined in the context of dilated cardiomyopathy. Recent results have demonstrated nuclear translocation of activated Akt correlates with prevention of dilation in mouse transgenic models of cardiomyopathy. The hypothesis of this proposal is that nuclear translocation of activated Akt inhibits the initiation and progression of dilation and heart failure. Insulin-like growth factor-1 (IGF-1) or the cellular oncogene Tcl-1 initiate nuclear translocation of Akt. In addition, we have discovered similar Akt activation by genistein, a phytoestrogen compound found in soy-based dietary products that exhibits estrogen agonist properties. Innovative approaches to be used involve mice that are genetically engineered or pharmacologically treated to activate Akt, with concurrent experiments to demonstrate beneficial effects of Akt activation in rescuing a transgenic mouse model of dilated cardiomyopathy.
The specific aims are: 1) to reproducibly and precisely induce Akt activation by IGF-1, genistein treatment, and Tcl-l expression; 2) to prevent pathologic and degenerative changes by activation of Akt; 3) to show that beneficial effects of Akt activation are dependent upon induction of phosphoinositide 3-kinase. Biochemical, molecular, and confocal microscopic approaches used in combination will demonstrate the efficacy of Akt activation by the various inductive stimuli as well as the impact of the different treatments upon the pathogenesis of dilation. The significance of the study is the identification and characterization of a therapeutic pathway for treatment of heart failure, along with new approaches for the activation of Akt in the heart. This study will demonstrate the relationship between Akt activation and inhibition of cardiomyopathy, providing novel directions for therapeutic treatment to induce Akt translocation and mitigate heart failure.
Kubli, Dieter A; Sussman, Mark A (2018) Editorial commentary: Mitochondrial autophagy in cardiac aging is all fluxed up. Trends Cardiovasc Med 28:261-262 |
Matsumoto, Collin; Jiang, Yan; Emathinger, Jacqueline et al. (2018) Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate. Stem Cells 36:868-880 |
Broughton, Kathleen M; Wang, Bingyan J; Firouzi, Fareheh et al. (2018) Mechanisms of Cardiac Repair and Regeneration. Circ Res 122:1151-1163 |
Broughton, Kathleen M; Sussman, Mark A (2018) Enhancement Strategies for Cardiac Regenerative Cell Therapy: Focus on Adult Stem Cells. Circ Res 123:177-187 |
Gude, Natalie A; Sussman, Mark A (2018) Chasing c-Kit through the heart: Taking a broader view. Pharmacol Res 127:110-115 |
Gude, Natalie A; Firouzi, Fareheh; Broughton, Kathleen M et al. (2018) Cardiac c-Kit Biology Revealed by Inducible Transgenesis. Circ Res 123:57-72 |
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686 |
Monsanto, Megan M; Wang, Bingyan J; Sussman, Mark A (2017) Synthetic MSC? Nothing Beats the Real Thing. Circ Res 120:1694-1695 |
Khalafalla, Farid G; Greene, Steven; Khan, Hashim et al. (2017) P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling. Circ Res 121:1224-1236 |
Fernández-Avilés, Francisco; Sanz-Ruiz, Ricardo; Climent, Andreu M et al. (2017) Global position paper on cardiovascular regenerative medicine. Eur Heart J 38:2532-2546 |
Showing the most recent 10 out of 94 publications