Left ventricular (LV) remodeling is a common adverse event following myocardial ischemia and reperfusion (I/R) and can result in LV failure and mortality. While this process is multifactorial, this laboratory and others have established that the induction of a family of extracellular matrix (ECM) proteolytic enzymes, the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling post-I/R. During the past performance period, we established that a unique membrane specific MMP, the membrane type-1 MMP (MT1-MMP), is increased following I/R. Since MT1-MMP possesses multiple biological actions and is robustly expressed on the myocyte sarcolemma, then it follows that MT1-MMP may play an important role in I/R injury. The release of bioactive signaling molecules such as endothelin (ET) occurs during and following I/R and was the focus of our studies during the last project performance period. Specifically, it was demonstrated that a surge of ET occurs within the myocardial ECM with I/R and was associated with an induction of a unique cassette of protein kinase C (PKC) isoforms. The central hypothesis of this ongoing research effort is that induction of a specific MMP type (MT1-MMP) occurs with I/R and that increased ET release into the myocardial ECM causes a PKC isoform dependent amplification of MT1-MMP. Using cell based studies, murine constructs, and a porcine I/R model, this hypothesis will be tested by accomplishing the following specific aims: (1) Demonstrate in an isolated LV myocyte system of I/R, that intracellular trafficking of MT1-MMP occurs which is regulated in part by ET receptor stimulation and activation of specific PKC isoforms. (2) Demonstrate in the intact murine system that ET regulates MT1-MMP induction with I/R and is a determinant of LV contractility. (3) Demonstrate increased regional interstitial ET causes MT1-MMP activation and LV dysfunction in a porcine I/R model, which is time dependent. The outcome from these integrated studies will identify a unique extracellular mechanism by which ET can contribute to regional LV dysfunction in the context of I/R and identify potential therapeutic targets to ameliorate 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. Following a heart attack, it is now clear that enzymes are made that continue to chew away at the heart muscle and eventually cause the heart to change shape and fail. This study will identify how to control a critical enzyme which causes the heart to fail following a heart attack and thereby develop new tests and treatments for patients after a heart attack.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057952-11
Application #
7841838
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
1998-01-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
11
Fiscal Year
2010
Total Cost
$368,750
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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
Graham, Eric M; Atz, Andrew M; McHugh, Kimberly E et al. (2014) Preoperative steroid treatment does not improve markers of inflammation after cardiac surgery in neonates: results from a randomized trial. J Thorac Cardiovasc Surg 147:902-8
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
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; Stolen, Craig M (2013) Biomarkers and heart disease: what is translational success? J Cardiovasc Transl Res 6:447-8
Spinale, Francis G; Janicki, Joseph S; Zile, Michael R (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112:195-208
Spinale, Francis G (2013) Epilysin (matrix metalloproteinase-28) joins the matrix metalloproteinase team on the field of postmyocardial infarction remodeling. Circ Res 112:579-82

Showing the most recent 10 out of 67 publications