Coronary artery disease can cause a prolonged period of reduced myocardial blood flow (ischemia) resulting in myocardial infarction (MI). However, paradoxically, re-establishing blood flow following a prolonged period of ischemia;termed ischemia-reperfusion (I/R), can in and of itself evoke a pathological process leading to LV dysfunction. Furthermore, patients with a pre-existing MI, which undergo a second I/R event are at much greater risk for LV dysfunction, morbidity and mortality. Increased release of the extracellular proteolytic enzymes, the matrix metalloproteinases (MMPs) occur with I/R and MI. Recently, we have demonstrated that a unique membrane specific MMP, the membrane type-1 MMP (MT1-MMP), is robustly expressed in cardiac fibroblasts and myocytes from patients, and is increased following I/R. Furthermore, our initial results have established that over- expression of MT1-MMP can exacerbate I/R injury. The central hypothesis of this project is that with I/R, increased interstitial MT1-MMP activity occurs which is dependent upon specific isoforms of the protein kinase (PKC) signaling pathway. Moreover, in the context of an existing MI, enhanced MT1- MMP induction occurs in the residual, viable myocardium causing a priming effect on overall MMP activity following a second episode of I/R, and directly contributes to LV dysfunction. We have developed a clinically relevant porcine model of I/R and will utilize this system to achieve the following aims. (1) Demonstrate a relationship between increased interstitial MT1-MMP activation and regional LV dysfunction which is PKC isoform dependent. (2) Demonstrate that enhanced MT1-MMP induction and activation occurs within the remote, viable myocardium following a defined MI- which will exacerbate regional LV contractility with a second period of I/R. (3) Demonstrate that regional modification of MT1-MMP expression will directly affect regional contractility following I/R. The outcome from these integrated studies will be to identify a unique extracellular mechanism contributing to LV dysfunction in the context of I/R with a particular focus on the clinically relevant condition of a previous MI and identify specific and novel therapeutic targets which will interrupt this process.

Public Health Relevance

One of the most common causes of death and disability in this country is from a heart attack;damage to the heart muscle. We have identified that a specific membrane bound enzyme is upregulated following a heart attack. Our intention is to understand how increased levels of this membrane enzyme can contribute to poor outcomes following a heart attack, and more importantly develop strategies to regulate this enzyme. These results will help develop new tests and treatments for patients suffering from heart failure after a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL095608-05
Application #
8653132
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Adhikari, Bishow B
Project Start
2010-01-15
Project End
2013-12-31
Budget Start
2013-01-03
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$322,799
Indirect Cost
$87,179
Name
University of South Carolina at Columbia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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
Kholmukhamedov, Andaleb; Logdon, Christina; Hu, Jiangting et al. (2014) Cyclosporin A in left ventricular remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 306:H53-9
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
Eckhouse, Shaina R; Jones, Jeffrey A; Spinale, Francis G (2013) Gene targeting in ischemic heart disease and failure: translational and clinical studies. Biochem Pharmacol 85:1-11

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