In the heart, as in cancer, metabolism provides energy and building blocks for the cell. James Watson (of The Double Helix fame) recently pronounced that in cancer, targeting metabolism may be a more promising approach to treatment than targeting transforming genes. At a time when cellular regeneration receives much attention, the intracellular dynamics of metabolism must be considered as well. In earlier work supported by this grant, we identified two metabolic signals serving as regulators of protein turnover in the heart: a low [ATP] / [AMP] ratio as regulator for protein degradation, and glucose 6-phosphate as regulator of the mTOR growth signaling pathway. We learned that in the heart, like in cancer cells, a phenomenon known as the Warburg Effect drives metabolic rearrangements which are linked to enable cell growth. Perhaps even more importantly, we learned that the oncometabolite D-2-hydroxyglutarate impairs cardiac function by inhibiting a Krebs cycle enzyme. Our overall objective is now to solidify the concept of a link between cancer cell metabolism, and cardiac cell metabolism, cardiac structure, and cardiac function independently from any chemotherapeutic agents or pharmacological interventions.
Specific Aim 1 will define the role of oncometabolic signals as regulators of cardiac remodeling.
Specific Aim 2 will define the role of reductive carboxylation as a mediator for metabolic structural and functional remodeling of the heart using the oncometabolite D-2-hydroxyglutarate as a model.
Specific Aim 3 will extend the findings to address specific structural, proteomic and epigenetic mechanisms of remodeling in the metabolically deregulated state of D-2- hydroxyglutarate. In summary, as we continue our work on the intracellular self-renewal of the cardiomyocyte, we expect to identify new regulatory proteins and enzymes that drive adaptation to metabolic stress in the heart. Our long-term goal is to develop a platform for new metabolic strategies to support the failing human heart by integrating specific, dynamic aspects of cancer cell metabolism with heart metabolism. In short, metabolic systems do not exist in isolation and their understanding may be exploited for the treatment of heart failure.
The defining feature of every cell is the dynamic state of its constituents. Our ongoing work on intracellular self- renewal of the heart has exposed two metabolic pathways, which are prominent in cancer cells and which weaken the heart in the absence of any chemotherapeutic agents. Based on shared features of metabolism we are now proposing to exploit dynamics of metabolic pathways to improve both structure and function of the failing heart.
|Stoll, Barbara J; Taegtmeyer, Heinrich (2018) Challenges for Today's Pediatric Physician-Scientists. JAMA Pediatr 172:220-221|
|Eblimit, Zeena; Thevananther, Sundararajah; Karpen, Saul J et al. (2018) TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice. Cardiovasc Ther 36:e12462|
|Nam, Deok Hwa; Kim, Eunah; Benham, Ashley et al. (2018) Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function. FASEB J :fj201800602R|
|Taegtmeyer, Heinrich; Karlstaedt, Anja (2018) Letter by Taegtmeyer and Karlstaedt Regarding Article, ""Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiov Circulation 137:986-987|
|Maack, Christoph; Lehrke, Michael; Backs, Johannes et al. (2018) Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J 39:4243-4254|
|Chen, Guobao; Bracamonte-Baran, William; Diny, Nicola L et al. (2018) Sca-1+ cardiac fibroblasts promote development of heart failure. Eur J Immunol 48:1522-1538|
|Brewer, Rachel A; Collins, Helen E; Berry, Ryan D et al. (2018) Temporal partitioning of adaptive responses of the murine heart to fasting. Life Sci 197:30-39|
|Karlstaedt, Anja; Schiffer, Walter; Taegtmeyer, Heinrich (2018) Actionable Metabolic Pathways in Heart Failure and Cancer-Lessons From Cancer Cell Metabolism. Front Cardiovasc Med 5:71|
|Rowlett, Veronica W; Mallampalli, Venkata K P S; Karlstaedt, Anja et al. (2017) Impact of Membrane Phospholipid Alterations in Escherichia coli on Cellular Function and Bacterial Stress Adaptation. J Bacteriol 199:|
|Desai, Moreshwar S; Mathur, Bhoomika; Eblimit, Zeena et al. (2017) Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 65:189-201|
Showing the most recent 10 out of 103 publications