Download Cardiac extracellular matrix: a dynamic entity

Am J Physiol Heart Circ Physiol 289: H973–H974, 2005;
doi:10.1152/ajpheart.00443.2005.
Editorial Focus
Cardiac extracellular matrix: a dynamic entity
Lindsay Brown
School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
UNDERSTANDING THE REGULATION of the extracellular matrix of
the heart is essential to understanding the chronic changes in
heart function in disease states such as hypertension, heart
failure, and diabetes. This understanding relies on overturning
the concept that the extracellular matrix of the heart is inert. As
a structural protein, the major role of collagen, a major component of the extracellular matrix, was considered as replacement of necrotic myocytes. This concept was derived from
early research on the heart that logically emphasized an understanding of the properties of cardiomyocytes, the cells that
develop force. Nutrient supply and waste product removal
from these myocytes required detailed investigations of the
vasculature of the heart so that studies on the extracellular
matrix started relatively late. Pioneering studies on the extracellular matrix by Borg, Caulfield, and Robinson in the late
1970s and early 1980s identified a complex fibrillar collagen
network in the heart. The complex physiological role of the
extracellular matrix includes connecting myocytes, aligning
contractile elements, preventing overextending and disruption
of myocytes, transmitting force, and providing tensile strength
to prevent rupture (22). Excessive collagen clearly is detrimental to cardiac function. Weber and colleagues (22) have shown
convincingly that collagen deposition can be controlled by
hormones such as angiotensin II and aldosterone. Chronic
activation of the renin-angiotensin system is associated with
the appearance of inflammatory cells and fibroblasts in the
perivascular space, preceding the changes to the vasculature,
leading to a perivascular fibrosis (20). Infarct tissue, predominantly collagen, is not inert but is dynamic, living tissue that
is cellular, vascularized, metabolically active, and contractile
(18, 21).
The extracellular matrix is a complex mixture of collagen
fibrils, elastin, cells including fibroblasts (6) and macrophages,
macromolecules such as glycoproteins, and glycosaminoglycans together with other molecules such as growth factors,
cytokines, and extracellular proteases. In this issue of the
American Journal of Physiology-Heart and Circulatory Physiology, Bouzeghrane and colleagues (2) have hypothesized that
fibrillin is also a constituent of the myocardium interstitium
that is regulated during the development of cardiac fibrosis.
This glycoprotein is deficient in Marfan’s syndrome, a severe
autosomal dominant trait affecting the cardiovascular system,
eyes, skeleton, dura, lungs, skin, and integument caused by
mutations of the fibrillin-1 gene (FBN1). Death frequently
results from dissection or rupture of the ascending aorta.
Deficient fibrillin-1 content has been implicated in the matrix
disruption of patients with bicuspid aortic valves by triggering
matrix metalloproteinase production (9). Bouzeghrane and colleagues (2) have shown that fibrillin is abundant throughout the
rodent myocardium as thin fibers that cross over the perimy-
Address for reprint requests and other correspondence: L. Brown, School of
Biomedical Sciences, The University of Queensland 4072, Brisbane, Australia
(e-mail: [email protected]).
http://www.ajpheart.org
sium and around arteries. Fibrillin increased in the interstitium
and accumulated in microscopic scars after the induction of
cardiac fibrosis by angiotensin II or deoxycorticosterone acetate. Furthermore, angiotensin II and transforming growth
factor-␤1 enhanced the synthesis of fibrillin by cardiac fibroblasts. These results strongly suggest that fibrillin is an important component of the extracellular matrix of the myocardium
that is upregulated during the development of cardiac fibrosis.
This study has used rodents to suggest potentially important
changes in human disease. Are these findings unique to the
rodent heart and thus not relevant to the human heart, especially in chronic cardiovascular disease? Of course this can
only be answered by appropriate studies on human myocardium, especially in patients with chronic hypertension or heart
failure. However, previous studies showing that angiotensinconverting enzyme (ACE) inhibitors prevented or reversed
cardiac fibrosis in angiotensin II-infused or deoxycorticosterone acetate-treated rats (4, 19) have been confirmed by elegant
studies in patients treated with lisinopril (3). This strongly
suggests that the human heart will show similar responses in
the extracellular matrix to the rodent heart.
The demonstration of fibrillin throughout the normal myocardium suggests a unique role for this component of the
matrix, possibly to transmit force from myocytes to the extracellular matrix. One potential role would be the regulation of
the stiffness or compliance of the heart. Collagen is a wellknown regulator of myocardial stiffness, and cross-linking of
the collagen strands is a key determinant (16). Bioengineering
research could provide the necessary insights into the role of
fibrillin as it has with the role of collagen in the mechanical
function of the heart (8, 10, 12). These studies have developed
three-dimensional representations of cardiac muscular architecture to investigate issues such as force development, electrical activation throughout the myocardium, and shear properties. Although these studies have emphasized the role of the
collagen network, the techniques would also be useful to define
the role of fibrillin in cardiac function in both normal function
as well as in pathophysiological states such as cardiac fibrosis.
The definition of perivascular fibrillin deposition suggests that
vascular function may also be regulated by changes in fibrillin
deposition, possibly changing vascular stiffness and endothelial function.
The molecular trigger for the increased expression of fibrillin is unknown. One suggestion would be reactive oxygen
species such as superoxide or its product hydrogen peroxide
formed by the action of superoxide dismutase. Both angiotensin II and endothelin, the hormones increased following angiotensin II infusion or deoxycorticosterone acetate-salt administration (7, 14) in the rat models used in this study, stimulate
production of superoxide by NADPH oxidase (13). Superoxide
stimulated collagen production by cardiac fibroblasts (17);
tempol, a superoxide dismutase mimetic, or losartan, an AT1
receptor antagonist, prevented NADPH-generated superoxide
production and aldosterone-induced fibrosis (11). An increased
endothelin-1 concentration acting through ET-A receptors has
0363-6135/05 $8.00 Copyright © 2005 the American Physiological Society
H973
Editorial Focus
H974
been shown to be a major cause of the hypertrophy and fibrosis
in the deoxycorticosterone acetate-salt hypertensive rat because these changes could be prevented by administration of
the selective ET-A receptor antagonist A-127722 (1). In deoxycorticosterone acetate-salt hypertensive rats, the impaired
vasodilator responses to acetylcholine were decreased following suppression of superoxide formation by sesamin (15).
The increased fibrillin deposition in cardiac fibrosis suggests
this process as a potential target for therapeutic intervention in
chronic cardiovascular disease. Many interventions have been
shown to decrease collagen production or increase collagen
breakdown (5); it seems logical to determine whether these
interventions are selective for collagen or also apply to fibrillin
expression or deposition. Possibly the most useful interventions for control of collagen deposition involve inhibition of
the actions of either angiotensin II or endothelin. Selective
agents, especially the ACE inhibitors as well as AT1 and ET-A
receptor antagonists, are now widely available for these studies. The use of these inhibitors and antagonists would also help
define the pathophysiological consequences of an increased
fibrillin expression and deposition.
In summary, Bouzeghrane and colleagues (2), by showing
the presence of fibrillin in rodent hearts and its upregulation in
models of cardiac fibrosis, have demonstrated the dynamic
complexity of the extracellular matrix. Furthermore, they have
added a potential target molecule for the understanding and
modification of cardiac function in both the normal and diseased heart.
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289 • SEPTEMBER 2005 •
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