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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Adhikari, Bishow B
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University of South Carolina at Columbia
Anatomy/Cell Biology
Schools of Medicine
United States
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