Matrix metalloproteinases: from biology to therapeutic strategies in cardiovascular disease.
In this comprehensive review of matrix remodeling, one central theme that bears re-emphasis is the extensivecross-talk and dynamic interactions that exist between terminally differentiated, postmitotic cells, proliferative cells, and the ECM of the cardiovascular system. The activities of MMPs and TIMPs constitute a well-orchestrated contest to maintain tissue integrity and homeostasis. Overexpression of MMPs tilts the balance in favor of irreversible tissue destruction of joints (eg, as in rheumatic disease), and efforts to curtail such errant pathways are ongoing (123). Thrombolytic therapy and percutaneous transluminal coronary angioplasty represent effective strategies for restoring antegrade flow in occluded vessels, but multiple factors preclude most patients with AMI from receiving either of these treatments. Tissue healing and remodeling is a process in which the biology of MMPs becomes universally applicable. Basic lessons from the biochemistry and enzymology of MMPs, combined with the mechanisms of gene expression, will undoubtedly impact the development of future therapies involving MMPs and their endogenous inhibitors. In addition, formidable challenges, ranging from bioavailability to tissue penetration and toxicity in animal models, face investigators using existing pharmacotherapeutics. For congenital diseases, such as Marfan syndrome, which primarily affects the connective tissue, future therapies may be targeted to the underlying pathobiology involving MMPs. Strategies aimed at correction of the genetic defect may be complemented by those to prevent or ameliorate fundamental imbalances in matrix turnover and deposition. The future challenge for cardiovascular medicine is to appropriately shift the pendulum, not to the exclusion of, but to the recognition of the dynamic interaction that exists between myocyte and nonmyocyte populations, which clearly affect the pathogenesis of many acquired and genetic disorders.
Benjamin
I J
IJ
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75390-8573, USA. ivor.benjamin@utsouthwestern.edu
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology; D002318:Cardiovascular Diseases / Q000209:etiology / Q000628:therapy*; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D008382:Marfan Syndrome / Q000209:etiology / Q000628:therapy; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000502:physiology*; D013379:Substrate Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology; D014945:Wound Healing
D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases