Investigating Novel Mechanisms Regulating Translation in the Normal and Diseased Heart

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

The overall goal of this project is to understand the mechanisms regulating translational changes in human heart failure. This work is currently focused on the prolyl hydroxylase OGFOD1, which is 2-oxoglutarate- and iron-dependent oxygenase domain protein 1. OGFOD1 has been previously shown to regulate translation in immortalized, cultured cell lines. Additionally, OGFOD1 has also been shown to function in the cellular ischemic stress response. Lending clinical relevance to understanding the role of OGFOD1 in the myocardium, published data also indicates OGFOD1 is up-regulated in human heart failure, which we were able to validate in preliminary studies. Based on this evidence supporting the significance of OGFOD1, our short-term goal is to investigate the potential for OGFOD1 to regulate translation in the heart, and for this regulation to be a key component of the cardiac response to stress. We are addressing these research aims using several key tools. First, we have an induced pluripotent stem cell line in which OGFOD1 has been deleted (OGFOD1-KO). This cell line is very useful for understanding the role of OGFOD1 in cardiomyocyte differentiation and maturation, and can also be differentiated into other cell types expressed in the heart, such as smooth muscle cells. The other model we use is a global knockout mouse in which OGFOD1 has been deleted (OGFOD1-KO). This OGFOD1-KO mouse is currently being used to test the role of OGFOD1 in heart failure and the pathologies leading to heart failure. In this project investigating the role of OGFOD1 in conditions that lead to heart failure, we have found that OGFOD1 deletion is protective in ex vivo and in vivo ischemia-reperfusion injury. Upon doing proteomics and metabolomics on OGFOD1-KO hearts and normal mouse hearts (wildtype or WT), we found that OGFOD1 deletion led to significant protein and metabolite changes that support alterations in purine and pyrimidine metabolism. When we measured different metabolites within these pathways using an independent detection method, we found that purine metabolism wasn't altered during ischemia. We then focused on pyrimidine metabolism, and found that carnosine seemed to be altered, and functioned in ischemia in a manner that supported a role for carnosine in the protection we observed in OGFOD1-KO mouse hearts. We are currently investigating whether OGFOD1 functions in other pathologies that can lead to heart failure such as cardiac hypertrophy, and the potential for this its role within this context to be directed through the cell stress response.