Diabetic cardiomyopathy is a heart failure syndrome that occurs in up to 50% of type 2 diabetics, and is a major contributor to mortality in this large population. This cardiomyopathy is characterized by diastolic dysfunction with hypertrophy that frequently transitions to gross systolic heart failure. Despite its clinical importance, the underlying basis of this syndrome is unknown. An important clue is that pathogenesis is strongly linked to hyperglycemia, but the absence of a pathway connecting hyperglycemia to downstream pathophysiological events has been a roadblock to progress in the field. We have discovered a new signaling pathway that may constitute an important piece of the puzzle. Hyperglycemia is known to induce the expression of Txnip (thioredoxin-interacting protein) in rodent and human hearts in vivo through a previously delineated transcriptional mechanism. Txnip has several traditional functions including (a) binding to and inhibition of thioredoxins, which are scavengers of reactive species, thereby resulting in oxidative stress; and (b) binding to and inactivation of glucose transporters, which functions as a protective mechanism during hyperglycemia. A third less studied action of Txnip is to induce apoptosis, including in cardiomyocytes, an event that could contribute to the transition from diastolic dysfunction to systolic heart failure in diabetic cardiomyopathy. However, the molecular pathway by which Txnip induces apoptosis is not known. In an unbiased proteomics screen, we found that Txnip unexpectedly interacts with Bax, an important mediator of cell death. Further, increased Txnip levels (as would be seen in diabetes) conformationally activate Bax and induce apoptosis in cardiomyocytes. Moreover, Txnip-induced apoptosis in the mouse heart in vivo is Bax- dependent. These results define the outlines of a Txnip-Bax pathway that may provide a link between hyperglycemia and the transition to systolic heart failure in diabetic cardiomyopathy. The goals of this project are to delineate the molecular nature of this pathway and to test its rol in diabetic cardiomyopathy in vivo.
Aim 1 evaluates three potential mechanisms by which Txnip activates Bax: (a) the Txnip-Bax interaction; (b) Txnip-mediated inhibition of thioredoxins, resulting in oxidative post-translational modifications of Bax that cause its activation; and (c) Txnip-mediated inhibition of glucose transporters resulting in metabolic stress and Bax-mediated cell death.
Aim 2 employs inducible, cardiomyocyte-specific Txnip and Bax knockout mice to test the overall significance of the Txnip-Bax pathway in diabetic cardiomyopathy in vivo. In addition, by genetically reconstituting the hearts of Txnip and Bax knockout mice with informative Txnip and Bax mutants, this aim tests the roles of the specific molecular mechanisms linking Txnip and Bax in diabetic cardiomyopathy in vivo. Elucidation of a pathway connecting hyperglycemia to cardiomyopathy would be a highly significant advance. Moreover, these studies possess high innovation as the pathway we are proposing was not previously known. The resulting knowledge may provide a basis for future specific therapies for diabetic cardiomyopathy.
Diabetic cardiomyopathy is a common and lethal heart failure syndrome whose basis is not known. We have discovered a new signaling pathway that connects hyperglycemia (the major metabolic abnormality in diabetes) with heart failure. This project will delineate critical molecular aspects of this pathway and its role in the pathogenesis of diabetic cardiomyopathy.
|McKimpson, Wendy M; Zheng, Min; Chua, Streamson C et al. (2017) ARC is essential for maintaining pancreatic islet structure and ?-cell viability during type 2 diabetes. Sci Rep 7:7019|
|Shires, Sarah E; Kitsis, Richard N; Gustafsson, Åsa B (2017) Beyond Mitophagy: The Diversity and Complexity of Parkin Function. Circ Res 120:1234-1236|
|Moslehi, Javid; Amgalan, Dulguun; Kitsis, Richard N (2017) Grounding Cardio-Oncology in Basic and Clinical Science. Circulation 136:3-5|
|McKimpson, Wendy M; Kitsis, Richard N (2017) A New Role for the ER Unfolded Protein Response Mediator ATF6: Induction of a Generalized Antioxidant Program. Circ Res 120:759-761|
|Amgalan, Dulguun; Pekson, Ryan; Kitsis, Richard N (2017) Troponin release following brief myocardial ischemia: apoptosis versus necrosis. JACC Basic Transl Sci 2:118-121|
|Amgalan, Dulguun; Chen, Yun; Kitsis, Richard N (2017) Death Receptor Signaling in the Heart: Cell Survival, Apoptosis, and Necroptosis. Circulation 136:743-746|
|Myers, Ronald B; Fomovsky, Gregory M; Lee, Samuel et al. (2016) Deletion of thioredoxin-interacting protein improves cardiac inotropic reserve in the streptozotocin-induced diabetic heart. Am J Physiol Heart Circ Physiol 310:H1748-59|
|Nah, Jihoon; Fernández, Álvaro F; Kitsis, Richard N et al. (2016) Does Autophagy Mediate Cardiac Myocyte Death During Stress? Circ Res 119:893-5|