Fundamental to the study of myocardial growth and the response to injury is an understanding of the elements involved in cardiac-specific gene regulation. To this end, studies have led to the discovery of a number of novel transcription factors that are responsible for both the cell and stage-specific induction of cardiomyocyte-specific proteins. Investigations into the factors involved in the repression of cardiac- specific genes, may be equally important and may provide insight into the definition of factors that maintain the differential myocardial phenotype as well as the mechanism(s) involved in the transition from the hypertrophic to the failing heart.
Our aim i s to explore the mechanism(s) of a specific stimulus associated with the repression of the myocyte-specific gene program, the cytokine interleukin-1 (IL-1). These investigations are particularly relevant since IL-1 is produced during circumstances characterized by alternations in both myocardial function and contractile protein expression. In this regard, previous work in our laboratory has found that IL-1beta induces a unique hypertrophic phenotype in culture that mimics in many ways that seen during the transition from hypertrophy to failure. While investigating the mechanism(s) of IL-1beta repression, we have found that, for several genes, the IL-1beta, effect co-localizes with that of the negative regulator yin yang-1 (YY1). In addition, IL-1beta is also associated with a decrease in the expression of transcription factors classically associated with the induction of myocyte-specific genes during development. It is the hypothesis of the present proposal that IL-1beta represses the promyogenic gene program of the cardiac myocyte through a complex series of actions on both a specific inhibitory transcription factor, yin yang-1 (YY1) as well as on several myogenic determination factors. In order to address this hypothesis the following aims have been identified: I. To characterize the effects of IL-1beta on the transcriptional program of the cardiac myocyte. II. To determine the mechanism of IL-1beta action on the negative regulator YY1. III. To evaluate the expression/activity of IL-1/YY1 in the adult heart under circumstances associated with myocardial dysfunction/failure.
| Long, C S (2001) The role of interleukin-1 in the failing heart. Heart Fail Rev 6:81-94 |
| Patten, M; Wang, W; Aminololama-Shakeri, S et al. (2000) IL-1 beta increases abundance and activity of the negative transcriptional regulator yin yang-1 (YY1) in neonatal rat cardiac myocytes. J Mol Cell Cardiol 32:1341-52 |
| Koudssi, F; Lopez, J E; Villegas, S et al. (1998) Cardiac fibroblasts arrest at the G1/S restriction point in response to interleukin (IL)-1beta. Evidence for IL-1beta-induced hypophosphorylation of the retinoblastoma protein. J Biol Chem 273:25796-803 |
