[Frontiers in Bioscience 14, 699-716, January 1, 2009]

Activation of MMP-2 as a key event in oxidative stress injury to the heart Mohammad A.M. Ali1, Richard Schulz1,2

1Department of Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada, 2Department of Pediatrics, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Nitrogen and oxygen derived free radicals in the heart
3.1. Free radical synthesis
3.2. Physiological roles of reactive oxygen species
3.3. Pathological targets of reactive oxygen species
4. Intracellular activity and targets of MMPs: a pathway triggered by oxidative stress
4.1. MMPs: Classification and structure
4.2. Regulation of MMPs activity
4.2.1. Transcriptional regulation
4.2.2. Post-transcriptional regulation
4.2.3. Post-translational modification
4.2.4. Compartmentalization
4.2.5. Endogenous inhibitors
4.3. Role of MMPs in cardiac physiology
4.4. Role of MMPs in cardiac pathology
4.5. Novel intracellular targets of MMP-2 in cardiomyocyte
4.5.1. Localization of MMP-2 to the sarcomere
4.5.2. Localization of MMP-2 to cytoskeletal proteins
4.5.3. Localization of MMP-2 to the nucleus
5. Novel therapeutics in cardiovascular disease
6. Conclusions
7. References

1. ABSTRACT

Oxygen and nitrogen derived free radicals play a crucial role in both cardiac physiology and pathology. In this review we discuss how these molecules interact in the cardiac cell, some aspects of their physiological importance, and their pathological effects with a special focus on the activation of matrix metalloproteinases (MMPs) as an early event in oxidative stress damage. MMPs are a family of zinc-dependent endopeptidases which play an active role in regulating the extracellular matrix. Recently, however, it has been recognized that MMPs may also rapidly act on intracellular substrates on a minutes timescale. This review will consider some recent developments in the intracellular localization and novel substrates of MMP-2 within the heart. In addition, we will discuss MMP inhibition as a novel therapeutic strategy to prevent oxidative stress damage to the heart.