Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors.
Basic pharmacological/transgenic studies have clearly demonstrated a cause-effect relationship between the induction and activation of matrix metalloproteinases (MMPs) and adverse changes in the structure and function of the left ventricle (LV). Thus, regulation of MMP induction and/or activation would appear to be a potential therapeutic target in the context of cardiovascular disease, such as following myocardial infarction (MI). However, pharmacological approaches to inhibit MMPs have yet to be realized for clinical applications. The endogenous inhibitors of the MMPs (TIMPs) constitute a set of 4 small molecules with unique functionality and specificity. Thus, improved understanding on the function and roles of individual TIMPs may provide important insight into the design and targets for pharmacological applications in LV remodeling processes, such as MI. Therefore, the purpose of this review will be to briefly examine biological functions and relevance of the individual TIMPs in terms of adverse LV remodeling post-MI. Second is to examine the past outcomes and issues surrounding clinical trials targeting MMPs in the post MI context and how new insights into TIMP biology may provide new pharmacological targets. This review will put forward the case that initial pharmacological attempts at MMP inhibition were over-simplistic and that future strategies must recognize the diversity of this matrix proteolytic system and that lessons from TIMP biology may lead to future therapeutic strategies.
Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia, SC, USA; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA; WJB Dorn Veteran Affairs Medical Center, Columbia, SC, USA. Electronic address: cvctrc@uscmed.sc.edu.
Francis G
FG
Spinale
Division of Cardiology, University of California-San Diego School of Medicine, La Jolla, CA, USA.
Francisco
F
Villarreal
D000818:Animals; D055786:Gene Knockout Techniques; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
Fibroblasts; Myocardial infarction; Myocardial remodeling; Tissue inhibitors of matrix metalloproteinases