title: Hypothesis: Metalloproteinase Inhibitors Decrease Risks of Cardiovascular Disease.
abstract: The hypothesis that matrix metalloproteinase (MMP) inhibitors reduce risks of cardiovascular disease in humans is plausible, unproven, and difficult to test, due, in part, to differences in specificity and route of administration. Endogenous tissue inhibitors of metalloproteinases (TIMPs) are tight-binding, protein inhibitors that function in vivo and can be engineered to enhance specificity for desired targets. Nonetheless, TIMPs have been difficult to test, in part, because their secondary functions, including cell growth promotion and angiogenesis, raise concerns about side effects and they cannot be delivered orally. In contrast, doxycycline and other chemically modified tetracyclines are broad-spectrum, reversible MMP inhibitors with lower affinity but can be taken orally and have US Food and Drug Administration approval. The completed phase 2 randomized trials in humans of MMP inhibitors have methodologic limitations but generally show no significant benefits with adverse effects. At present, the principal research challenge is to achieve a better understanding of the complexities of biological functions of MMPs and subsequently to conduct large-scale phase 3 trials.
authors.affiliation: Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lizotte-Waniewski
authors.affiliation: Department of Basic Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Brew
authors.affiliation: Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA chenneke@health.fau.edu.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Hennekens
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D002317:Cardiovascular Agents; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
keywords: acute myocardial infarction; cardiovascular disease; heart failure; molecular biology