Changes in cardiomyocyte size and energy utilization occur in a variety of clinical scenarios, including myocardial infarction, pressure overload, metabolic stress, and in some genetic conditions. Although much is now known about the signaling pathways that regulate adaptive and maladaptive responses to stress in cardiomyocytes, little is known about how these pathways are coupled to mandatory changes in protein turnover that are requisite during adaptive cardiomyocyte responses, nor do we understand how these events are coupled to changes in myocardial energy utilization. These unanswered questions represent a major gap in our understanding of the pathophysiology of cardiovascular disease. Our laboratory has identified critical roles for ubiquitin ligases in regulating cardiomyocyte cell function and cardiac responses to stress. CHIP (carboxy-terminus of Hsc70-interacting protein) was cloned and characterized by our laboratory in 1999, and we have recently shown that this protein has a key role in regulating protein quality control in the setting of cellular and physiologic stress, such as myocardial infarction. More recently, we have found that 2 other ubiquitin ligases, atrogin and MuRF1 (muscle ring-finger protein 1) are responsible for antagonizing cardiomyocyte signaling in the setting of hypertrophic stress, in part through targeted degradation of cardiomyocyte signaling and structural proteins. These proteins therefore provide ideal models for understanding how cardiomyocytes adapt to stress and how cell size is regulated and maintained in pathophysiologic circumstances.
The aims of this grant are intended as a logical extension of our initial project designed to elucidate the role that cardiac-specific ubiquitin ligases atrogin 1 and MuRF1 play in provoking cardiac hypertrophy and regulating adaptive responses in the setting of cardiomyocyte stress.
The specific aims of this proposal are to: (1) Contrast the roles of MuRFs 1-3 in the setting of myocardial ischemia;(2) Assess the molecular and cellular roles of MuRF family proteins in mediating metabolic adaptation to myocardial ischemia;and (3) Characterize the cellular relationships between MuRF family members and turnover of cardiomyocyte proteins. To accomplish these aims we have formulated a novel and highly integrated approach using both in vitro and in vivo assays. The scope of this proposal is intended to address relevant biological and physiological questions using state of the art molecular biology techniques. In addition to providing a new basis to appreciate the role of targeted protein turnover as a key regulatory mechanism in cardiomyocyte biology, these studies will help us to predict whether these proteins represent new potential targets for intervention in diseases associated with abnormal regulation of cardiomyocyte volume.
Being able to adapt to both physiological and pathophysiological stressors is essential for cardiomyocyte health and proper cardiac function. However, modes of adaptation in these highly specialized cells are limited due to the fact that mitotic events within cardiomyocytes occur at an exceptionally low level in humans. Hence, changes in cell size and metabolism are among the few adaptations available to the heart as it responds to stress. Although much is now known about the signaling pathways that regulate adaptive and maladaptive responses to stress in cardiomyocytes, little is known about how these pathways are coupled to mandatory changes in protein turnover that are requisite during adaptive cardiomyocyte responses, nor do we understand how these events are coupled to changes in myocardial energy utilization. These unanswered questions represent a major gap in our understanding of the pathophysiology of cardiovascular disease. Our overall goal is to determine how cardiac-specific ubiquitin ligases regulate adaptive responses in the setting of cardiomyocyte stress. These studies will help us predict whether ubiquitin ligases represent a new class of therapeutic targets in the fight against diseases associated with abnormal regulation of cardiomyocyte volume.
|Kim, Sung-Mi; Grenert, James P; Patterson, Cam et al. (2016) CHIP(-/-)-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications. Sci Rep 6:29423|
|RodrÃguez, Jessica E; Liao, Jie-Ying; He, Jun et al. (2015) The ubiquitin ligase MuRF1 regulates PPARÎ± activity in the heart by enhancing nuclear export via monoubiquitination. Mol Cell Endocrinol 413:36-48|
|Xie, Liang; Pi, Xinchun; Wang, Zhongjing et al. (2015) Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. J Mol Cell Cardiol 80:156-65|
|Xie, Liang; Pi, Xinchun; Townley-Tilson, W H Davin et al. (2015) PHD2/3-dependent hydroxylation tunes cardiac response to Î²-adrenergic stress via phospholamban. J Clin Invest 125:2759-71|
|Schisler, Jonathan C; Grevengoed, Trisha J; Pascual, Florencia et al. (2015) Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. J Am Heart Assoc 4:|
|Willis, Monte S; Wadosky, Kristine M; Rodriguez, Jessica E et al. (2014) Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo. Cell Biochem Funct 32:39-50|
|Xu, Lei; Yates, Cecelia C; Lockyer, Pamela et al. (2014) MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition. J Mol Cell Cardiol 77:86-101|
|Willis, Monte S; Patterson, Cam (2014) Protein quality control, the ubiquitin proteasome system, and autophagy: when worlds collide. [Corrected]. J Mol Cell Cardiol 71:1-2|
|Dyer, Laura; Pi, Xinchun; Patterson, Cam (2014) Connecting the coronaries: how the coronary plexus develops and is functionalized. Dev Biol 395:111-9|
|Pi, Xinchun; Xie, Liang; Portbury, Andrea L et al. (2014) NADPH oxidase-generated reactive oxygen species are required for stromal cell-derived factor-1Î±-stimulated angiogenesis. Arterioscler Thromb Vasc Biol 34:2023-32|
Showing the most recent 10 out of 38 publications