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.
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.
|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|
|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|
|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|
|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|
|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|
|Spinale, Francis G; Janicki, Joseph S; Zile, Michael R (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112:195-208|
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