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Matrix Metalloproteinase Inhibitors as Investigative Tools in the Pathogenesis and Management of Vascular Disease

  • Mina M. Benjamin
  • Raouf A. Khalil
Chapter
Part of the Experientia Supplementum book series (EXS, volume 103)

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolytic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune disease, and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only one MMP inhibitor, i.e., doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.

Keywords

Aneurysm Angiogenesis Atherosclerosis Endothelium Extracellular matrix Hypertension Preeclampsia Pregnancy TIMP Varicose veins Vascular smooth muscle 

Abbreviations

AAA

Abdominal aortic aneurysm

ADAM

A disintegrin and metalloproteinase

BP

Blood pressure

EC

Endothelial cell

ECM

Extracellular matrix

FGF

Fibroblast growth factor

GPCR

G-protein-coupled receptor

HUVECs

Human umbilical vein endothelial cells

IGF

Insulin-like growth factor

MAPK

Mitogen-activated protein kinase

MMP

Matrix metalloproteinase

MI

Myocardial infarction

NO

Nitric oxide

Phe

Phenylephrine

PKC

Protein kinase C

TGF

Transforming growth factor

TIMP

Tissue inhibitor of matrix metalloproteinase

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

VSM

Vascular smooth muscle

Notes

Acknowledgments

This work was supported by grants from National Heart, Lung, and Blood Institute (HL-65998, HL-98724) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-60702).

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Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  1. 1.Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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