The pathophysiological understanding of chronic heart failure has shifted from a mere hemodynamic disorder to a much more complex syndrome including changes and imbalances in neurohormonal, immune, transcriptional and metabolic functions. Among the metabolic abnormalities, chronic heart failure has been associated with increased levels of uric acid (hyperuricemia), the end product of purine metabolism. Specifically, studies have shown a strong association between serum uric acid levels and cardiovascular morbidity and mortality, especially among individuals with high cardiovascular risk, including those with hypertension, diabetes and congestive heart failure. Abnormal purine metabolism is also known for its contribution to ROS production through xanthine oxidase, the final enzyme in this pathway, which is increasingly appreciated as an important contributor to both symptoms of chronic heart failure as well as progression of the disease. Indeed, therapeutic inhibition of increased xanthine oxidase activity (via allopurinol) in heart failure patients has been shown to counteract maladaptive chronic upregulation of purine metabolism with specific benefits observed in peripheral blood flow and decreased free oxygen radical generation, suggesting that targeting this pathway therapeutically can be beneficial for heart failure patients. However, the underlying mechanisms which drive these changes in purine metabolism in the cardiomyocyte and ultimately ROS and uric acid accumulation in heart failure patients remain largely unknown. We recently discovered that the methyltransferase Smyd1b, which displays unique roles in both the cytosol and nucleus, interacts with the metabolic enzyme Adss (Adenylossuccinate Synthatase), a key component of purine metabolism in the heart. We have confirmed this novel interaction between Smyd1b and Adss is enhanced during phenylephrine-induced hypertrophic growth in the cardiomyocyte and is associated with increased methylation of Adss. In addition, we have shown that Smyd1 enhances the enzymatic activity of Adss as it converts IMP to sAMP in vitro. Despite these intriguing results, how Smyd1 regulates Adss activity and its effect on purine metabolism and uric acid production is completely unknown. My fellowship application will utilize a unique genetic animal model and state-of-the-art proteomic technologies to conceptually advance our understanding of myocyte biology and physiology. Specifically, this work will determine the role of Smyd1 in regulating Adss activity in the adult heart, characterize its ability to influence ROS production and uric acid accumulation, and determine whether overexpression of Smyd1 can inhibit these deleterious processes. Together, my experiments will build upon our previous results and allow me to elucidate the specific molecular mechanism by which Smyd1b regulates purine metabolism in the heart and how this process is regulated under normal and hypertrophic conditions.
Heart disease has been characterized by compensatory changes in metabolic and transcriptional regulation which lead to catastrophic alterations at the cellular and organ level in the heart. The lysine methyltransferase Smyd1 has recently been shown to regulate growth and metabolic remodeling in the adult heart ? presumably through its methyltransferase activity ? however the specific molecular mechanisms by which it regulates these biological processes is largely unknown. I will investigate the transcript variant Smyd1b, in cardiomyocytes, to characterize its novel interaction with Adenylosuccinate synthetase and its downstream effects on key aspects of purine metabolism.
