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(Circulation. 2000;102:1874.)
© 2000 American Heart Association, Inc.

Editorial

Matrix Matters

Peter Libby, MD; Richard T. Lee, MD

From Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Peter Libby, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu

Key Words: Editorials • extracellular matrix • metalloproteinases • cells

Cardiologists have commonly conceived of the extracellular matrix as an inert collection of structural macromolecules that serve as a scaffold for cells. Rapidly accumulating evidence challenges this view. Matrix macromolecules can regulate key functions of cells, and the composition of the cardiovascular extracellular matrix is under strict control. These control mechanisms can act in a slow and almost imperceptible manner, causing long-term changes in tissue structure, but they can also be very rapid, facilitating almost immediate changes in cellular behavior. Here, we explore these new concepts in the context of certain common cardiovascular diseases.

Extracellular Matrix Can Control Cell Behavior

A large body of evidence supports a central role of the extracellular matrix in the control of numerous cellular functions (Table). Extracellular matrix molecules can ligate integrin molecules on the surface of cardiac myocytes, endothelial cells, and smooth muscle cells, as well as inflammatory cells that participate in important cardiovascular diseases. On ligation, integrin receptors can transduce signals that alter key cellular functions ("outside-in signaling").¹ Cells bound to different extracellular matrix substrates through integrins respond differently to growth factors and other stimuli. In the absence of signals arising from attachment to the extracellular matrix, cells can undergo apoptosis. A number of growth factors bind to extracellular matrix molecules, conferring biochemical stability to the growth factors and serving as a tissue reservoir of mitogens primed for release. Proteoglycans can function at the cell surface as coreceptors for growth factors like fibroblast growth factor-2² or within the interstitial space, where proteoglycans like versican and biglycan can bind lipoproteins.³ Indeed, binding to extracellular matrix can cause accumulation of LDL particles in the artery wall and render these particles more susceptible to oxidative modification. These processes probably contribute decisively to the initial phases of atherosclerosis. Thus, far from being mere structural cement that surrounds cells, the extracellular matrix is a dynamic, interactive milieu that sends signals that influence such critical cell functions as reproduction, life, and death.

View this table: [in this window] [in a new window]   Table 1. Selected Functions of the Cardiovascular Extracellular Matrix

Role of the Extracellular Matrix in Heart Failure

When subjected to a chronic volume overload, ventricular chambers remodel through dilatation. This remodeling process leads to gross changes in the overall quantity of ventricular extracellular matrix and probably also requires microscopic changes at the local pericellular space to repositioning of cells. The role of altered extracellular matrix metabolism in the volume-overloaded ventricle has received inadequate attention. However, in this issue of Circulation, Spinale et al⁴ show that some important members of the large cast of characters involved in extracellular matrix remodeling localize in the left ventricle failing due to chronic tachycardia induced by pacing. These failing hearts express members of the matrix metalloproteinase (MMP) family. They further exhibit overexpression of key regulatory molecules of MMP function, including extracellular matrix metalloproteinase inducer (EMMPRIN), which is an endogenous inducer of MMP expression, and the transmembrane metalloproteinse MT-1 MMP, which can bind and activate MMP-2.⁵

Although Spinale et al do not supply functional evidence of the involvement of these specific components of the MMP induction and activation system in matrix remodeling pacing–induced heart failure, these initial observations certainly raise the hypotheses that EMMPRIN and MT-1 MMP participate in ventricular dilation. Participants in extracellular matrix metabolism like MMPs frequently localize in injured or remodeling tissues, and observations of overexpression alone do not necessarily demonstrate that individual proteins play a crucial role in the process. For example, although MMPs are temporally and spatially regulated during development, most mice with targeted deletions of MMPs develop normally. However, when challenged with specific pathological stimuli, many of these genetically altered mice respond differently from control mice, suggesting a crucial role for MMPs in many diseases.⁶

Emerging evidence is providing rapid momentum to the concept that MMPs directly mediate crucial steps in the development of heart failure. Experiments from several laboratories, using different species and even different pharmacological inhibitors, indicate that inhibition of MMPs can block ventricular dilation.^{7 8 9} Furthermore, Kim et al¹⁰ demonstrated that transgenic overexpression of the human MMP-1 gene in the mouse ventricle leads to myocyte hypertrophy and ventricular dysfunction. Because MMP-1 is an important gene for initiation of the degradation of fibrillar collagen and is missing in the mouse genome, these data indicate that MMPs may directly mediate dilation and hypertrophy in some circumstances.

Extracellular Matrix Remodeling Participates in Altered Ventricular Geometry After Myocardial Infarction

Much evidence supports the extent of left ventricular remodeling as a critical determinant of clinical outcome after myocardial infarction. Indeed, ACE inhibitors forestall remodeling and reduce fibrosis of the infarcted ventricle, possibly crucial components of their clinical benefit. MMP levels rapidly increase in myocardium during infarction and remain elevated through the healing phase.¹¹ Inhibition of MMPs can limit ventricular remodeling after experimental myocardial infarction.⁸ Furthermore, infarcted mice with deletion of MMP-9, an enzyme that degrades collagen fragments as well as many other substrates, have reduced early myocardial rupture¹² as well as progressive ventricular dilation.¹³

Altered Extracellular Matrix Metabolism, a Critical Contributor to Arterial Pathology

Just as matrix metabolism figures importantly in myocardial remodeling, changes in the synthesis and degradation of the arterial extracellular matrix accompany vascular diseases. Decreased arterial compliance in hypertension and with aging correlates with accumulation of collagen and loss of elastin. Arterial pulse pressure, determined in part on the basis of arterial compliance, closely correlates with clinical outcome in certain patient groups. Accelerated arterial extracellular matrix breakdown influences the course of atherosclerosis at several stages. During the initial period of development of the atherosclerotic plaque, outward growth produces "compensatory enlargement." Like ventricular dilatation, this arterial enlargement must involve matrix remodeling. In the latter stages of atherosclerosis, thrombotic complications often result from disruptions of the atherosclerotic plaque due to rupture of the fibrous cap or superficial erosion of the endothelium. Both of these processes may depend in part on excessive extracellular matrix dissolution. Finally, aneurysm formation represents an extreme example of arterial remodeling. Substantial evidence suggests dysregulation of extracellular matrix metabolism in this form of arterial pathology as well.¹⁴

Extracellular Matrix Degradation: A Tightly Regulated Process

The work of numerous investigators, including the observations reported by Spinale et al,⁴ show strict control of the molecular mechanisms that underlie extracellular matrix breakdown. The MMPs, first synthesized as inactive zymogen precursors, require activation to attain enzymatic function. The endogenous tissue inhibitors of MMPs (TIMPs 1 to 4), which are also under tight transcriptional control, can hold these enzymes in check. Thus, the actual activity of MMPs depends on the rate of synthesis, activation, and the balance between active enzyme and inhibitors (Figure). In addition, matrix catabolism in the cardiovascular system involves enzymes other than the MMP family. For example, elastolytic cathepsins may play crucial roles in atherosclerosis and aneurysm formation. These enzymes, like the MMPs, require activation and have endogenous inhibitors, the cystatins, and recent studies have demonstrated an imbalance between cathepsin S and its inhibitor, cystatin C, in atherosclerosis and aneurysm.¹⁵

View larger version (26K): [in this window] [in a new window]   Figure 1. Multiple levels of control of activity of extracellular MMPs. MMPs, first synthesized as inactive zymogen precursors, require processing to gain enzymatic activity. Cleavage of "pro" portion of nascent protease can occur autocatalytically or heterocatalytically, involving other MMPs, including MT-MMP, thrombin, or reactive oxygen species in the case of MMP-2. Cleavage or unfolding of pro portion of molecule renders active site of enzyme able to access substrates and degrade them. Ubiquitously distributed tissue inhibitors of MMPs (TIMPs 1 to 4) can bind to active protease, blocking active site, and rendering enzyme inactive. Thus, control of MMP activity depends on gene transcription, translation, posttranslational control of zymogen activation, and balance between proteases and their endogenous inhibitors, TIMPs.

Conclusion

This brief discussion highlights the critical role of extracellular matrix in the control of cardiovascular function. Far from being an inert cement, the matrix is under dynamic and exquisite control. Dysregulation of extracellular matrix metabolism modulates major features of myocardial and arterial pathology. This recognition provides new insight into the pathogenesis of cardiovascular diseases and further illustrates new potential targets for intervening.

Footnotes

Drs Libby and Lee conduct research funded by Pfizer in a related area. In addition, Dr Libby serves on the Scientific Advisory Board of British Biotech, Ltd.

References

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