Heart failure (HF) is a major health epidemic in developed countries, however, its underlying pathology is not well characterized. A hallmark of HF is derangement of metabolic processes in cardiomocytes, including lipid metabolism, the main energy source of cardiac tissue. Tristetraprolin (TTP, originally discovered to be regulated by insulin) is a tandem zinc finger protein that binds to AU-rich elements (ARE) in the 3'-untranslated region (UTR) of target mRNA molecules, and induces their degradation. TTP knockout (KO) mice display systemic inflammation due to its role in the degradation of TNF? mRNA, thus very few studies have assessed the role of TTP in metabolism. We recently showed that TTP regulates cellular iron by conserving this metal for essential proteins. In addition, our preliminary studies suggest that TTP regulates fatty acid (FA) metabolism, and binds to and regulates the mRNA of a key protein in this processes, peroxisome proliferator- activated receptor (PPAR)-? in cardiomyocytes. The central hypothesis of this proposal is that TTP regulates cardiac FA metabolism through downregulation of PPAR?. We also propose that deletion of cardiac TTP is protective against the development of HF due to its effects on FA metabolism.
In Aim 1, we will assess whether TTP regulates cardiac FA metabolism by binding to PPAR? mRNA and promoting its degradation. We will assess FA metabolism in cardiac cells with TTP knockdown (KD) and hearts from global and cardiac-specific TTP KO (csTTP-KO) mice, and will determine whether these changes are through PPAR? using TTP/PPAR? double KO approach. We will also assess whether TTP directly regulates PPAR? by performing deletion studies of its 3'-UTR AREs, RNA co-IP, and mRNA stability assays.
In Aim 2, we will determine whether TTP plays a role in the development of HF and whether this is dependent on PPAR? metabolism. We will subject global and csTTP-KO mice and their littermate controls to pressure overload and coronary ligation and assess their cardiac function and metabolism.
Cardiac cells alter their metabolism in response to changes in their environment, especially in the setting of Heart Failure. The mechanisms for these changes in cardiac metabolism are not fully understood, but certain proteins are believed to regulate this process. In this proposal, we will determine how a novel protein called tristetraprolin (TTP) regulates cardiac metabolism, and how it plays a role in the changes seen in heart failure.
| De Jesus, Adam; Chang, Hsiang-Chun; Ardehali, Hossein (2018) Metabolic Suppression of HIF-1? Contributes to Susceptibility of Ischemic Injury in Diabetic Hearts. JACC Basic Transl Sci 3:499-502 |
