Download Fibrosis in dilated cardiomyopathy, part II

Article
"Development of the European Network in Orphan Cardiovascular Diseases"
„Rozszerzenie Europejskiej Sieci Współpracy ds Sierocych Chorób Kardiologicznych”
Title: Fibrosis in dilated cardiomyopathy, part II
RCD code: III-1B.1 (ICD-10 code I42.7)
Author: Paweł Rubiś1,2,
Affiliation:
1
Department of Cardiac and Vascular Diseases, John Paul II Hospital, Institute of Cardiology
2
Center for Rare Cardiovascular Diseases, John Paul II Hospital
Background
The control of ECM remodeling is on multiple levels. One of the most important controlling
mechanisms are non-structural matricellular proteins, such as osteopontin (OPN) and tenascin-C (TNC). Osteopontin, which was originally detected in osteoblast and osteoclastas, and thanks to cytokinelike properties, has been implicated in a variety of biological processes, mainly chemotaxis, wound
repair, and remodeling. OPN is secreted by numerous cells, such as fibroblasts, macrophages, and Tcells. In the normal, unstressed human myocardium, OPN is not expressed but under pathologic
conditions becomes up-regulated.
In the cardiovascular system, OPN was found to be a key molecule, mediating LV remodeling,
vascular and valvular calcification. In an experimental model of myocarditis, OPN mRNA was
detected in infiltrating macrophages. In another murine model of myocarditis, it was elegantly shown
by immunohistochemistry that OPN had an affinity to necrotic and fibrotic areas, where it is probably
responsible for chemotaxis of macrophages and T-cells and the transformation of fibroblasts into
myofibroblasts – the source of ECM structural proteins. In OPN knockout mice less fibrosis was
observed which was associated with more benign course of mycocarditis and rare progression to
DCM.
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
Discussion
Published data on the association of OPN and cardiac diseases are rather limited. In patients
with histopathologically and immunohistologically proven myocarditis, OPN mRNA expression was
found in all biopsies (as measured by quantitative RT-PCR and in situ hybridization). Osteopontin
mRNA expression was considerably decreased in the follow-up biopsies if myocarditis was healing,
whereas, it was persistently increased when myocarditis was transforming into chronic disease. In the
same study it was observed that OPN mRNA was not detected in biopsies of patients with DCM. In
contrast, in another study of DCM patients high OPN expression, that correlated with collagen type I,
was observed.
The role of circulating OPN is slightly better studied. Soluble OPN concentrations are
increased in patients with rheumatic mitral stenosis, stable and unstable angina, and myocardial
infarction. In one study, patients with acute myocardits had higher plasma levels of OPN compared
with patients with DCM and hypertrophic cardiomyopathy. A rapid decline in OPN plasma levels was
correlated with myocarditis healing and absence of cardiac inflammation in the follow-up biopsies as
well as an improvement in clinical symptoms and LV systolic function.
Although numerous uncertainties exist, it seems that OPN plays an important role in the early
phases of ECM changes during acute myocardits but loses significance when active myocardial
inflammation recedes. Furthermore, the role of OPN in DCM is unknown. From a practical point of
view, the relatively easy access to plasma OPN may result in OPN utilization as a non-invasive marker
of myocardits activity. In an experimental study of viral myocardits, treatment of infected mice with
vitamin D analog led to decreased myocardial expression levels of OPN, MMP-3 and TIMP-1, which
translated into reduced fibrosis. Thus, OPN may serve as a diagnostic tool as well as a potential
therapeutic target to limit cardiac remodeling in myocarditis and DCM.
Similarly to OPN, little or no tenascin-C is detected in healthy adult tissue. However, it is
transiently re-expressed upon tissue injury and down-regulated after tissue repair is complete.
Tenascin-C is only expressed in the heart in early embryo where contributes to the development of
myocardium. Tenascin-C expression was documented at very early stages of an experimental
myocardits. The high TN-C expression was maintained during healing and remodeling process but
was not detected in subsequent scar tissue. However, data on human pathology indicate persistent TNC expression with prolonged inflammation and tissue remodeling. In humans TN-C is re-expressed not
only in acute states, such as myocarditis, myocardial infarction but also in chronic diseases, including
hypertension, DCM or end-stage HF. Tenascin-C is specifically localized to sites of inflammatory cell
infiltration and active fibrosis but was undetected in healed tissue. In murine models of myocarditis,
TN-C was found to help to recruit and differentiate fibroblast and myofibrobalsts and stimulate their
ECM production. A quantitative analysis of the percentage of collagen revealed that ECM deposition
was significantly reduced in mice that do not express TN-C. Likewise, in DCM, TN-C was associated
with areas of prolonged inflammation and fibrosis but was not present in healed (scar) tissue. It was
found that areas with a high expression of TN-C were associated with accelerated fibrosis and
remodeling in comparison to the sites where TN-C expression was lower.
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
Conclusion
The molecular mechanisms by which TN-C exert theses effects on heart repair are not clear.
There are only few experimental studies suggesting a close relationship between TN-C and MMP.
Moreover, in a single study in humans, serum TN-C and MMP-9 levels were both elevated in patients
with ongoing remodeling but were reduced in patients who responded well to CRT-reversal of
remodeling. On the other hand, circulating serum TN-C has been showed to correlate with poor
prognosis and mortality in myocardial infarction, DCM, and HF.
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John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu