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.
One of the leading causes of death and disability in the VA patient population is the development and progression of heart failure. A common underlying cause of heart failure is from long standing high blood pressure which will result in the heart muscle becoming thickened with an increase in scar- like tissue- which is called fibrosis. Heart fibrosis will result in the inability of the heart to accept blood and as a result, these patients will be severely weakened, and often require hospitalization. As a consequence of the aging population, the incidence of heart failure is predicted to increase at an alarming rate resulting in a significant strain on medical care delivery systems; in particular the VA. One major hurdle that must be overcome to improve treatment and prevention of this form of heart failure, is to identify the pathways which cause heart fibrosis. This study will identify a novel protein that is likely to be central in the early development of heart fibrosis, secondary to hypertension and heart failure. These studies will set the stage for developing novel methods to identify patients at risk for developing this form of heart failure as well as targets for interrupting the inexorable progression to heart failure in the vulnerable VA patient population.
|Spinale, Francis G; Frangogiannis, Nikolaos G; Hinz, Boris et al. (2016) Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research. Circ Res 119:1040-1045|
|Gopinathannair, Rakesh; Etheridge, Susan P; Marchlinski, Francis E et al. (2015) Arrhythmia-Induced Cardiomyopathies: Mechanisms, Recognition, and Management. J Am Coll Cardiol 66:1714-28|
|Eckhouse, Shaina R; Purcell, Brendan P; McGarvey, Jeremy R et al. (2014) Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction. Sci Transl Med 6:223ra21|
|Goldsmith, Edie C; Bradshaw, Amy D; Zile, Michael R et al. (2014) Myocardial fibroblast-matrix interactions and potential therapeutic targets. J Mol Cell Cardiol 70:92-9|
|McGarvey, Jeremy R; Pettaway, Sara; Shuman, James A et al. (2014) Targeted injection of a biocomposite material alters macrophage and fibroblast phenotype and function following myocardial infarction: relation to left ventricular remodeling. J Pharmacol Exp Ther 350:701-9|
|Spinale, Francis G; Villarreal, Francisco (2014) Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem Pharmacol 90:7-15|
|Purcell, Brendan P; Lobb, David; Charati, Manoj B et al. (2014) Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat Mater 13:653-61|
|Zavadzkas, Juozas A; Stroud, Robert E; Bouges, Shenikqua et al. (2014) Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice. Circ Res 114:1435-45|
|Zile, Michael R; Baicu, Catalin F; Stroud, Robert E et al. (2014) Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload. Circ Heart Fail 7:340-50|
|Spinale, Francis G; Janicki, Joseph S; Zile, Michael R (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112:195-208|