Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI) and is an important predictor of clinical outcomes. Increased inductions of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), occur in the early and late phases of post-MI remodeling. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens have hindered clinical progress. During our past performance period, we have successfully moved the field forward in terms of demonstrating that localized delivery of a hyaluronic acid based hydrogel (HA-gel) and release of an MMP inhibitory peptide could effectively attenuate adverse post-MI remodeling. We now propose to further advance the translational and clinical relevance of these proof of concept studies and ?repurpose? MMP inhibitors that were advanced clinically by overcoming past obstacles regarding systemic delivery and specificity. Our guiding hypothesis is that using a novel self-assembling HA-gel, which will release a pharmacological MMP inhibitor selectively into the MI region, will effectively and favorably alter the course of adverse post-MI remodeling. We will first establish that localized injection of an HA- gel/MMP inhibitor construct will reduce regional local MMP activity, attenuate post-MI regional remodeling and fibroblast transdifferentiation, and thereby prevent the progression of LV pump failure. Next, we will demonstrate that targeted injection of an HA-gel/MMP inhibitor construct will cause favorable effects on the natural history of post-MI remodeling, whether injected early or late post-MI. Finally, we will advance the translational relevance of these studies by demonstrating the beneficial effects of the HA-gel/MMP inhibitor construct using novel delivery methods. These studies will provide the pivotal pre-clinical information in order to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent heart failure.
Over the past 10 years, we have identified that a specific enzyme system that 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 specific 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|
|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|