Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, invariably occurs following a myocardial infarction (MI) and contributes to clinical outcomes. The ECM plays a critical role in the maintenance of LV geometry and function, and increased induction of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs) occur with MI and contribute to LV remodeling. We have established that a unique MMP type, the membrane type-1 MMP (MT1-MMP), is increased following MI, and that overexpression accelerates post-MI remodeling. Recent studies from this laboratory and others have identified that MT1-MMP may actually facilitate ECM synthesis by processing profibrotic signaling molecules, such as transforming growth factor-beta (TGF). Our new results have identified that MT1-MMP processes the latent TGF binding protein-1 (LTBP-1), potentially augmenting ECM synthesis/accumulation. However, to move the field forward in terms of cause-effect between MT1-MMP induction and adverse LV remodeling, as well as establishing a therapeutic target, will require novel transgenic constructs and most importantly targeted, selective MT1-MMP inhibition. In this project continuation, we will move our basic discoveries forward and utilize ou newly developed MT1-MMP targeting techniques in order to test the hypothesis that while MT1-MMP activation occurs within the MI region as well as the remote viable myocardium, distinctly different proteolytic events occur - favoring myocardial matrix instability within the MI region an accelerated fibrosis within the remote region. Thus, selective targeting of MT1-MMP induction in a region, temporal, and cell specific fashion will directly alter the course of LV remodeling. The following aims will be addressed: (1) Discovery of MT1-MMP Heterogeneity: Demonstrate a regional heterogeneity in myocardial MT1-MMP substrate processing and establish that region specific fibroblast transformation and persistent MT1-MMP expression occurs. (2) Establishing MT1-MMP Mechanisms by Transgenesis: Establish cell specific targeting of MT1-MMP will alter the course of LV remodeling post MI. We will utilize both myocardial and fibroblast specific alterations in MT1-MMP levels following MI. (3) Demonstrating MT1-MMP as a Therapeutic Target: Using a validated regional injection method, whereby the MT1-MMP inhibitor is contained within a hydrogel, establish that selective and regional MT1-MMP inhibition will alter the course of adverse LV remodeling. Through a stepwise and combinatorial translational approach, a proteolytic pathway contributing to heterogeneous LV remodeling post-I/R will be established and will identify both interstitial signaling and intracellular pathways that can serve as potential therapeutic targets to favorably modify this process. These findings hold relevance to ECM remodeling/fibrosis pathways in general and are of particular relevance to adverse LV remodeling which occurs within the VA patient population.
Over the past 10 years, we have identified that a specific enzyme system which degrades structural proteins within the heart muscle is upregulated following a heart attack. This study will determine how interruption of this enzyme system by local injection of specifically designed molecules, will improve heart structure and function following a heart attack. This study is the first to use these new local target approaches which will provide specifi treatment to the heart, but not cause side-effects- a problem with medications that are given by mouth or injection. These studies will directly demonstrate the utility of a new strategy for preventing patients from developing heart failure. These results will set the stage for an entirely new treatment approach for patients suffering from heart failure after a heart attack.
|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|
|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|
|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|
|Spinale, Francis G; Janicki, Joseph S; Zile, Michael R (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112:195-208|