The mature mammalian myocardium can be divided conceptually into two interdependent cellular compartments. The contractile compartment, made-up of cardiac myocytes, and the interstitial compartment made-up predominantly by cardiac fibroblasts. Although initially thought to serve a predominantly """"""""structural"""""""" role in myocardial function, the cells and extracellular matrix (ECM) of the interstitial compartment have been increasingly found to play an active role in both normal and abnormal myocardial growth. In contrast to the cardiac myocyte, whose replicative capacity is limited in the adult heart, the cardiac fibroblast retains the ability to proliferate and does so in response to many pathologic circumstances. The cardiac fibroblast is the major source of both EMC production and many of the cytokines with potent effects on myocyte growth, fibroblast proliferation, and matrix homeostasis. As such, understanding the mechanisms of fibroblast growth control could lead to novel therapeutic approaches to myocardial disease states. Indeed, recent large scale trials of both interventional (i.e. PTCA) and pharmacologic (i.e. ACE inhibitors) interventions after myocardial injury have provided compelling evidence that the degree of hemodynamic compromise is related to the extent of interstitial """"""""remodeling"""""""" that occurs. Despite the obvious importance of the cardiac fibroblast in myocardial repair, however, there is little information available on either the kinetics of the fibroblast cell cycle, or the factors that regulate its initiation. In order for the cardiac fibroblast to become such a """"""""target"""""""" for therapeutic manipulation, however, the fundamental mechanisms that regulate its entry into and exit from the cell cycle must be identified. The overall hypothesis being examined is that interleukin-1 beta (IL-1 beta), a cytokine produced locally in response to myocardial injury, plays an important role in the subsequent repair and remodeling of the cardiac interstitium. This conclusion is based upon both historical data on cytokine and ECM gene expression during myocardial repair, and our investigations indicating that IL-1 beta has potent effects on cardiac fibroblast proliferation. The specific hypothesis being tested in the work proposed is that IL-1 beta prohibits fibroblast entry into the cell cycle by activating the p27KIP1 kinase inhibitor. To address this hypothesis several Specific Aims have been identified: 1) Determine the universal nature of the IL-1 beta inhibition of fibroblast proliferation, 2) Fully characterize the cell cycle-specific targets of IL-1 beta action on cardiac fibroblast proliferation, 3) Identify the role of cyclin dependent kinase inhibitors in the IL-1 beta-mediated effect, 4) Characterize the post-receptor signaling pathway responsible for IL-1 beta inhibition, and 5) Determine the characteristics of fibroblast cell cycle kinetics and gene expression in an in vivo model of post-infarction myocardial injury.
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