Heart failure is the major cause of cardiovascular mortality in the US and often develops as a consequence of maladaptive cardiac remodeling due to hypertension or a myocardial infarction (MI). Although over the past decade we have made major advances in the treatment of heart failure, the morbidity and mortality associated with this disease remains high. Thus, the identification of candidate proteins and signaling pathways that prevent or reverse the process of maladaptive cardiac remodeling is a major goal in the pursuit of new treatment approaches for improving the quality and longevity of heart failure patients. Our laboratory recently identified cytoglobin (Cygb) as a stress-responsive hemoprotein and its levels increase in the adult heart under a variety of stress conditions (i.e. hypoxia, ischemia, and pressure-overload). Overexpression of Cygb in cultured myocytes protects them from oxidative stress, while knockdown of Cygb results in increased apoptotic cell death. Initially, we postulated that Cygb protects myocytes via anti-oxidative mechanisms inherent to all hemoproteins;however, we now have extensive evidence that Cygb is also directly involved in regulating the transcriptional activity of the tumor suppressor protein p53. W have found a reciprocal relationship between transcript levels of Cygb and a number of p53-target genes. Chromatin immunoprecipitation experiments demonstrate co-occupancy of p53 and Cygb at classic p53 target promoters. Using recombinant proteins we show a direct protein-protein interaction between the two proteins. Importantly, recombinant Cygb inhibits p53 transcriptional activity in vitro reconstituted transcriptional assays. Finally, we have developed conditional Cygb knockout mouse model and have preliminary studies demonstrating that acute cardiac-specific loss of Cygb leads to a dilated cardiomyopathy. Likewise, mice born with cardiac-specific deletion of Cygb develop a more pronounced dilated cardiomyopathy after ischemia-reperfusion (I/R) injury as compared to injured control mice. Our central hypothesis is that Cygb contributes to cardiomyocyte survival via both anti-oxidative and p53-dependent mechanisms. We propose the following three specific aims to test this hypothesis:
Specific Aim 1 : Define the role of cytoglobin in maintaining cardiomyocyte homeostasis.
Specific Aim 2 : Define the role of cytoglobin during maladaptive cardiac remodeling.
Specific Aim 3 : Define the significance of the cytoglobin-p53 interaction for cardiomyocyte survival. The successful completion of our proposed study will provide insight into a novel signaling pathway that regulates cardiomyocyte survival and may provide opportunities for the development of novel therapeutic approaches to prevent and/or reverse heart failure. Thus, the proposed NIH R01 Research Grant Application is relevant to and in keeping with the missions of both the NIH and NHBLI.
The experiments proposed in this NIH R01 Research Grant Application have significant relevance to the public health of the nation. This study is innovative because it proposes that cytoglobin, a novel stress-responsive cardiac hemoprotein, plays an important role in promoting cardiomyocyte survival and thus may regulate the development of maladaptive cardiac remodeling. Ultimately, an enhanced understanding of the cellular function of cytoglobin within the heart will provide opportunities for the development of novel therapeutic approaches to prevent and/or reverse the development of maladaptive cardiac remodeling and thus improve the outcomes of heart failure patients.
|Sun, Yuxiao; Yao, Xiao; Zhang, Qing-Jun et al. (2018) Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. Circulation 138:2247-2262|
|Azcutia, Veronica; Bassil, Ribal; Herter, Jan M et al. (2017) Defects in CD4+ T cell LFA-1 integrin-dependent adhesion and proliferation protect Cd47-/- mice from EAE. J Leukoc Biol 101:493-505|
|Parra, Valentina; Rothermel, Beverly A (2017) Calcineurin signaling in the heart: The importance of time and place. J Mol Cell Cardiol 103:121-136|
|Canseco, Diana C; Kimura, Wataru; Garg, Sonia et al. (2015) Human ventricular unloading induces cardiomyocyte proliferation. J Am Coll Cardiol 65:892-900|
|Wang, Zhao V; Deng, Yingfeng; Gao, Ningguo et al. (2014) Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156:1179-1192|
|Singh, Sarvjeet; Canseco, Diana C; Manda, Shilpa M et al. (2014) Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration. Proc Natl Acad Sci U S A 111:E129-38|
|Hunt, James M; Bethea, Brian; Liu, Xiang et al. (2013) Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease. Am J Physiol Lung Cell Mol Physiol 305:L725-36|
|Thibodeau, J T; Rao, M P; Gupta, C et al. (2013) Health insurance as a requirement to undergo cardiac transplantation: a national survey of transplant program practices. Transplant Proc 45:360-3|
|Quintens, Roel; Singh, Sarvjeet; Lemaire, Katleen et al. (2013) Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS One 8:e56719|
|Porrello, Enzo R; Mahmoud, Ahmed I; Simpson, Emma et al. (2013) Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc Natl Acad Sci U S A 110:187-92|
Showing the most recent 10 out of 13 publications