Maladaptive Remodeling in Aging Myocardium

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Project Summary/Abstract A common cause for the development and progression of HF in the elderly is hypertension, which causes a pressure overload resulting in hypertrophy (LVH). While LVH is a complex multifactorial process which involves changes in myocardial growth and metabolism, a common structural event is increased extracellular matrix (ECM) accumulation (ie fibrosis). One of the important observations from this past research period was that a unique MMP type, the membrane type-1 MMP (MT1-MMP) was associated with significant ECM accumulation, particularly within the aging myocardium. One potent profibrotic pathway is transforming growth factor (TGF) which is held in an inactive form by the latency-associated TGF binding protein-1 LTBP-1. Our preliminary studies demonstrate that MT1-MMP processes LTBP-1, which would yield an active form of TGF. Thus, the central hypothesis of this continuing research project is that increased induction and expression of MT1-MMP causes an amplified profibrotic cascade which is a molecular cornerstone of ECM accumulation with LVH; particularly within the aging myocardium. This project will perform a step-wise set of studies that will use novel transgenic constructs which will allow for the quantitation of MT1-MMP promoter activity, proteolytic activity, LTBP-1 processing, and most importantly regulate MT1-MMP expression during the progression of LVH and with aging. Moreover, this study will demonstrate that regional regulation of MT1-MMP induction and activity directly changes the course of myocardial fibrosis that occurs within the aging myocardium; particularly with the superimposition of LVH. The results from these proposed studies will identify a novel proteolytic pathway which regulates ECM accumulation in the context of developing LVH, and thereby provide new critical insights into how ECM accumulation- ie fibrosis can occur within the aging myocardium, in particular with a pressure overload stimulus. These studies will identify a novel proteolytic pathway which contributes to ECM accumulation within the aging myocardium and the development of LVH; thereby defining molecular targets for improved diagnostic and therapeutic strategies for elderly patients at risk for LVH induced HF.