Ontogeny of enhanced decorin levels and distribution within myocardium of failing hearts

The proteoglycan, decorin, is a regulator of collagen fibril organization and its resulting functional properties. The temporal and spatial expression of decorin during the progression to heart failure is not well understood and may play a significant role in extracellular matrix remodeling. Decorin and types I and III collagen levels were measured in male Spontaneously Hypertensive Heart Failure (SHHF) and control Wistar-Furth rats at 2 and 8 mo, and at congestive heart failure (CHF). Decorin levels increased in the SHHF rats relative to the control rats in CHF. Type I collagen levels increased while type III levels decreased in the SHHF rats in CHF relative to the age matched controls. The SHHF rats have 48 and 45 KDa isoforms of the decorin core protein expressed at all ages while control Wistar-Furths produced only a 45 KDa form. Decorin was localized in the outer ventricle wall but during CHF, decorin was expressed throughout the ventricular myocardium. Immunogold localization of decorin demonstrated an increased distribution of decorin along the myocardium collagen fibrils at CHF. The enhanced expression and greater distribution of decorin may be linked to extracellular matrix remodeling which occurs with the development of heart failure.     

Influence of collagen-fibril-based coatings containing decorin and biglycan on osteoblast behavior

Collagen is used as a scaffold material for tissue engineering as well as a coating material for implants with a view to enhancing osseointegration by mimicry of the bone extracellular matrix in vivo. The biomimicry strategy can be taken further by incorporating the small leucine-rich proteoglycans (SLRPs) decorin and biglycan, which are expressed in bone. Both bind to fibrils during fibrillogenesis in vitro. In this study, the ability of collagen types I, II, and III to bind decorin and biglycan was compared. Collagen type II bound significantly more SLRPs in fibrils than collagen I and III, with more biglycan than decorin bound by all three collagen types. Therefore, type II fibrils with bound decorin or biglycan or neither were used to coat titanium surfaces. Bioavailability of SLRPs was confirmed by direct ELISA after SLRP biotinilation. The in vitro behavior of osteoblasts from rat calvaria (rOs) and human knee (hOs) cultured on different surfaces was compared. Proliferation and collagen synthesis were determined. Also, the influence of SLRPs on the formation of focal adhesions by rO was investigated. Biglycan enhanced the formation of focal adhesions after 2 and 24 h. Decorin and biglycan affected rO and hO proliferation and collagen synthesis differently. Biglycan stimulated hO proliferation significantly but had no effect on rO proliferation, and also inhibited rO collagen synthesis significantly while not affecting hO collagen synthesis. Decorin promoted hO proliferation slightly but did not influence rO proliferation. The results could be relevant when designing implant coatings or tissue engineering scaffolds.     

Endotoxinemia and systemic inflammation in pathogenesis of chronic heart failure

Large intestine microbiocenosis, levels of endotoxinemia, tumor necrosis factor alpha, C-reactive protein, sE-selectin, matrix metalloproteinase-9 (MMP) and tissue inhibitor of metalloproteinases-4 (TIMP) in chronic heart failure (CHF) patients was studied. Association of dysbiosis and endotoxinemia levels increase, systemic inflammation activation and an imbalance of MMP-TIMP system with progression of CHF has been shown. It can be a reason of a myocardium extracellular matrix structure disturbance and heart remodeling at CHF.     

Association between a cell-seeded collagen matrix and cellular cardiomyoplasty for myocardial support and regeneration

The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure.     

Structural change in decorin with skin aging

Decorin, the main proteoglycan in skin, has a small size with a core protein of approximately 40kDa and one chondroitin sulfate/dermatan sulfate glycosaminoglycan (GAG) chain. The main function of decorin is to regulate the collagen matrix assembly. Decorin is distributed along collagen fibrils with the core protein and the decorin GAG chain controls the distance between the collagen fibrils. Reducing the length of the decorin GAG chain reduces the distance between the collagen fibrils. Age-related changes in decorin are apparent in the GAG chain in respect to the molecular size and sulfate position but not in the core protein. Structural changes in the decorin GAG chain may be involved in changes in collagen matrix assembly during the aging process.     

Myocardial expression and redistribution of GRKs in hypertensive hypertrophy and failure

G-protein-coupled receptor kinases (GRKs) are involved in cardiac hypertrophy and failure. But their temporal expression and cellular localization during the development of hypertrophy and its transition to failure remains to be investigated. In this study, we determined the expression and subcellular distribution of GRK2, GRK3, GRK5, and GRK6 in cardiac myocytes of 2- to 24-month-old spontaneously hypertensive heart failure (SHHF) rats. GRK2 increased in the intercalated disks in 6-, 12-, and 24-month-old SHHF rats, although total expression remained relatively constant from 2 to 24 months in both SHHF and normotensive rats. GRK3 expression progressively increased in 6-, 12-, and 24-month-old SHHF rats and was significantly higher than in age-matched controls. Immunolabeling of GRK3 showed a typical pattern of cross-striations that colocalized with alpha-actinin and G(alphas) at Z-lines in both SHHF and control rats. GRK5 expression showed no change from 2 to 24 months in both SHHF and normotensive rats. Confocal analysis revealed nuclear translocation of GRK5 in myocytes of SHHF rats. GRK6 had a striated pattern colocalized with alpha-actinin at Z-lines in the cytoplasm and was also present in the intercalated disks of cardiac myocytes from both SHHF and control rats. GRK6 expression increased in 12- and 24-month-old SHHF rats and was significantly higher than in age-matched controls. GRK6 labeling was reduced at the intercalated disks, but increased in the cytoplasm of cardiac myocytes from SHHF rats compared to age-matched controls. The increased expression of GRK3 and GRK6 and subcellular redistribution of GRK2, GRK5, and GRK6 in SHHF rats may be involved in abnormal remodeling of cardiac myocytes in hypertensive hypertrophy and failure.     

Heart remodeling produced by aortic stenosis promotes cardiomyocyte apoptosis mediated by collagen V imbalance

Cardiac remodeling (CR) is a structural change of the heart due to chronic hemodynamic overload related to changes in both myocyte and extracellular matrix (ECM). We investigated that the imbalance of collagen V promotes cardiomyocyte apoptosis that contributes to heart failure and cell death. Aortic stenosis was induced surgically and male Wistar rats were randomized to 18 weeks (Sham 18?w, n?=?12; AoS 18?w, n?=?12) and severe of heart failure (Sham HF, n?=?12; AoS HF, n?=?12) groups. Functional and structural echocardiogram, immunohistochemistry for Ki-67, TUNEL assay and Immunofluorescence for collagen were performed. Our main results were: (1) Progressive reduction of cardiac functional capacity due to cardiac remodeling with decreased eject fraction in heart failure; (2) Imbalance of collagen deposition with increased, crowded and irregular collagen I in situ expression; (3) Dysregulation of dynamic control of collagen fibers with exposed epitopes of collagen V; (4) Additional apoptosis that are dependent to cardiac injury. The collagen V expression in cardiac remodeling is for the first time described and may be related to additional apoptosis and autoimmune response. Our findings suggest a critical role of collagen V in cardiac remodeling to modulate and promote heart failure and death.     

Structural Change in Decorin with Skin Aging

Decorin, the main proteoglycan in skin, has a small size with a core protein of ～ 40kDa and one chondroitin sulfate/dermatan sulfate glycosaminoglycan (GAG) chain. The main function of decorin is to regulate the collagen matrix assembly. Decorin is distributed along collagen fibrils with the core protein and the decorin GAG chain controls the distance between the collagen fibrils. Reducing the length of the decorin GAG chain reduces the distance between the collagen fibrils. Age-related changes in decorin are apparent in the GAG chain in respect to the molecular size and sulfate position but not in the core protein. Structural changes in the decorin GAG chain may be involved in changes in collagen matrix assembly during the aging process.     

Time-dependent changes of decorin in the infarct zone after experimentally induced myocardial infarction in rats: comparison with biglycan

Decorin, a small dermatan sulphate proteoglycan, has been postulated to interact with other components of the extracellular matrix. We examined time-dependent changes of decorin in the infarct zone after experimentally induced myocardial infarction in rats by Northern blotting, in situ hybridization, and immunohistochemistry. The expression of decorin mRNA was compared to that of biglycan mRNA. Northern blotting demonstrated that the decorin mRNA expression was not increased in the infarct zone on day 2, while increased biglycan mRNA was observed at that time (average 3.1-fold increase). Decorin mRNA expression was increased on day 7, and reached a peak (average 2.2-fold increase) around day 14. Biglycan mRNA expression also reached a peak level around day 14 (average 13.3-fold increase). In situ hybridization revealed that mRNA signals for decorin did not appear in the infarct zone on day 2, while biglycan mRNA signals were observed. Decorin mRNA signals were observed in spindle-shaped mesenchymal cells in the infarct peripheral zone on day 7. The decorin mRNA signals appeared later than those of biglycan. Immunopositive staining for decorin was observed in the infarct zone on day 7. The present results demonstrated a time-dependent increase in decorin mRNA expression in mesenchymal cells in the infarct zone in rats. Decorin mRNA appeared later and was increased to a lower extent in the infarct zone than biglycan mRNA.     

Induction of cardiac fibrosis by transforming growth factor-beta(1)

The role of transforming growth factor-beta(1) (TGF-beta(1)) in the production and deposition of collagens and in the induction of gene expression in the myocardium in relation to the development of myocardial fibrosis will be discussed. Very low expression of TGF-beta(1) and collagen type I and III mRNA is seen in the normal rat heart. Both expressions are markedly increased in the infarcted heart and the levels of TGF-beta(1) mRNA precedes increases in mRNA levels for extracellular matrix (ECM) proteins, suggesting a possible role of TGF-beta(1) in remodeling processes in the myocardium. The TGF-beta(1) expression is normally only transient since continuous TGF-beta(1) overexpression seems to promote nonadaptive cardiac hypertrophy and myocardial fibrosis. In vitro, TGF-beta(1) induces an increase in collagen production and secretion and enhances the abundance of mRNA levels for collagen type I and III in rat cardiac fibroblasts in culture. TGF-beta(1) also stimulates in vivo the expression of ECM proteins and in vivo gene transfer of TGF-beta(1) can induce myocardial fibrosis. Increased myocardial TGF-beta(1) and ECM protein mRNA are found in myocardial fibrosis induced by angiotensin II infusion, by noradrenaline treatment, by isoprenaline infusion, and by long-term blockade of NO synthesis. In vivo antagonism of TGF-beta(1) by neutralizing anti-TGF-beta(1) antibodies or by proteoglycans prevents the increase in gene expression of ECM proteins and inhibits myocardial fibrosis, suggesting that the increases in matrix protein production and fibrosis are mediated by TGF-beta(1).     

The absence of the embryo in the pseudopregnant uterus alters the deposition of some ECM molecules during decidualization in mice

The embryo-implantation promotes deep changes in the uterus resulting in the formation of a new structure at the maternal–fetal interface, the decidua. Decidualization can also be induced in pseudopregnant rodents resulting in a structure called deciduoma that is morphologically and functionally similar to the decidua. Previous studies from our and other laboratories demonstrate that in rodents, decidualization of the endometrium requires remarkable remodeling of the endometrial extracellular matrix (ECM) that is mainly coordinated by estradiol and progesterone. The influence of the embryo in this process, however, has not yet been investigated. To enlarge the knowledge on this subject, the present study investigates the behavior of a set of ECM molecules, in the absence of paracrine cues originated from the embryo. For that deciduoma was induced in pseudopregnant Swiss mice, and the distribution of collagen types I, III, IV, V and the proteoglycans decorin and biglycan was investigated by immunolabeling from the fifth to the eighth day of pseudopregnancy. It was observed the deposition of collagen types III and IV as well as decorin and biglycan was similar to that previously described by our group in the decidua. However, in the absence of the embryo, some differences occur in the distribution of collagen types I and V, suggesting that beside the major role of ovarian hormones on the endometrial ECM remodeling, molecular signals originated from the conceptus may influence this process.     

Cardiac remodeling and failure: from molecules to man (Part III).

Given the lack of a unified theory of heart failure, future research efforts will be required to unify and synthesize our current understanding of the multiple mechanisms that control remodeling in the failing heart. Matrix remodeling and the associated activation of inflammatory cytokines and MMPs have emerged as key pathways in the development of heart failure. As such, attempts to understand the integrated control of ECM homeostasis with the bioactivation of inflammatory cytokines may be of particular relevance to the development of effective anti-remodeling approaches. Notably, the implantation of isolated populations of cells in failing myocardium has a profound and consistent anti-remodeling effect that limits the progression to CHF. These observations were consistently identified in numerous studies using diverse experimental animal models and varied cell types. Accordingly, multicenter clinical trials are underway, and the preliminary data in patients with CHF are encouraging. Despite the enormous promise of cell transplantation to restore and regenerate failing myocardium, the mechanisms underlying these profound biological effects are not understood. An improved understanding of the myocardial response to cell implantation, particularly on parameters of matrix remodeling, may help unify our current understanding of the progression of heart failure and optimize the development of this technique for its evolving therapeutic use. The following review outlines recent advances in medical and surgical approaches to control the remodeling process that underlies the progression of heart failure.     

Induction of myocardial connective tissue growth factor in pacing-induced heart failure in pigs

AIMS: Connective tissue growth factor (CTGF) is a secreted, heparin-binding, and extracellular matrix associated protein shown to stimulate many of the cellular events underlying fibrosis. Previous investigations have revealed that myocardial CTGF is substantially induced in ischaemic heart failure, particularly in the ischaemic and peri-ischaemic region. The purpose of the present study was to investigate to what extent myocardial induction of CTGF is a general response to congestive heart failure (CHF) and to what extent CTGF is a decisive effector of fibrosis. METHODS: Experimental heart failure in pigs was induced by rapid pacing at 220-240 beats min(-1) for 3 weeks (CHF pigs; n = 12). RESULTS: The CHF pigs exhibited significant left ventricular (LV) dilatation, reduced contractility, and increased cardiac filling pressures. Northern blot analysis demonstrated that myocardial CTGF mRNA levels in CHF pigs were fivefold higher (P < 0.05) than those in control pigs (n = 10). Similar elevations of immunoreactive CTGF (sixfold; P < 0.05) were observed in myocardial tissue samples prepared for Western blot analysis. Immunohistochemical analysis of myocardial tissue sections revealed predominant expression in interstitial and perivascular fibroblasts and endothelial cells. Myocardial procollagen alpha1(I) mRNA levels were also significantly elevated (sixfold; P < 0.05) in CHF pigs compared with controls, whereas myocardial tissue contents of collagen were not statistically different between the groups. CONCLUSION: Induction of myocardial CTGF in heart failure is not just a response to ischaemia, but rather a general response to evolving heart failure. Yet, induction of myocardial CTGF was clearly not a sufficient effector of fibrosis.     

Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries.

Proteoglycans are important constituents of blood vessels and accumulate in various forms of vascular disease. Little is known concerning the proteoglycan composition of restenotic lesions formed after angioplasty and whether the proteoglycan composition of these lesions differs from that of primary atherosclerosis. Accordingly, we sought to characterize the distribution of two proteoglycans, biglycan and decorin, in primary atherosclerotic and restenotic lesions of human coronary arteries. Restenosis (n = 37) and primary (n = 11) lesions obtained from 48 patients by directional atherectomy of human coronary arteries were stained with antibodies against biglycan and decorin. To further characterize the extracellular matrix of restenotic tissues, we studied the co-distribution of these proteoglycans with collagen types I, III, and IV. The loose fibroproliferative tissue seen predominantly in restenosis lesions consistently stained positively for biglycan in patterns of deposition ranging from disseminated to homogeneous. The density and intensity of biglycan staining was correlated with the density of collagen type I and III fiber networks, both of which were observed to interweave among the loose fibroproliferative tissue. The compact connective tissue of primary atherosclerotic plaque was characterized by strong biglycan staining which co-localized with intense collagen type I and III staining. Only basement membrane-like structures rich in collagen type IV demonstrated negative biglycan staining. In contrast, loose fibroproliferative tissue exhibited no significant staining for decorin. Strong immunostaining for decorin, however, was found in primary atherosclerotic plaque. There are thus regional differences in the distribution of extracellular matrix proteoglycans of restenotic and primary human atherosclerotic lesions; these observations suggest that differences established for the biological roles of biglycan and decorin in other organ systems may extend as well to pathologically altered human coronary arteries.     

Effect of Decorin and Dermatan Sulfate on the Mechanical Properties of a Neocartilage

Decorin is known to influence the size of collagen fibrils in ligaments and tendons and it has been hypothesized to provide a structural link between collagen fibrils in connective tissues, including cartilage. Coincidently, mechanical properties of skin, ligament, and tendons are altered in decorin knockout mice, suggesting it may influence the structural properties of tissue or tissue matrix organization. To further examine the role of decorin in the extracellular matrix development and subsequent material properties of cartilage, tissue (neocartilage) was grown in a 3D culture model using a pure population of genetically modified chondrocytes stably overexpressing decorin (DCN) or decorin lacking dermatan sulfate (MDCN). An empty vector (CON) served as a virus control. Following generation of the cartilage-like tissues, mechanical properties in tension and compression, collagen fibril diameter, matrix organization, and biochemistry of the tissue were determined. There were no differences between CON and DCN tissues in any parameter measured. In contrast, tissue generated in MDCN cultures was thinner, had higher collagen density, and higher elastic moduli as compared to both CON and DCN tissues. Considering there was no difference in stiffness between CON and DCN tissues, the notion that decorin contributes to the mechanical properties via load transfer was refuted in this model. However, contrasts in the mechanical properties of the MDCN tissue suggest that the dermatan sulfate chains on decorin influences the organization/maturation and resultant mechanical properties of the matrix by as an yet-unidentified regulatory mechanism.     

β3肾上腺素能受体激动剂和抑制剂对心衰大鼠心室MMP2和9表达的影响

 目的 研究β3肾上腺素能受体(AR)激动剂和抑制剂对心衰(HF)大鼠左室基质金属蛋白酶2、9(MMP-2、MMP-9)表达的影响,明确β3AR在左室重构中的作用。方法 Wistar大鼠140只,随机分为对照组10只,余130只制备HF模型,选取心衰大鼠随机分为HF组(n=11)、激动剂组(n=12)、抑制剂组(n=10)。激动剂组、抑制剂组分别给予BRL37344 1.65?g/kg、SR59230A 50?g/kg尾静脉注射,2次/周。分别于4和8周时各组选取5只大鼠测定以下指标：心功能的相关指标、左室重量/体质量、心肌胶原容积分数、MMP-2、MMP-9蛋白和mRNA表达。结果 与对照组比较,HF组大鼠心功能明显下降,激动剂组随时间增加心功能恶化较HF组更明显,而抑制剂组心功能明显改善;与对照组比较,HF组MMP-2、MMP-9 mRNA、蛋白表达增高;激动剂组增加更明显; 拮抗剂组表达减少(均为P＜0.01)。结论 β3AR抑制剂改善心功能可能通过抑制心肌MMP-2、MMP-9表达来实现。     

Immune mechanisms in pathogenesis of chronic heart failure

In the review the new information about a participation of immune mechanisms in a pathogenesis of a chronic heart failure (CHF) is presented. Significance of a bacterial endotoxin, as inductor of activation of immune system at CHF, and factors of a system inflammation in a pathogenesis of the disease, breaking balance of matrix metalloproteinases and tissue inhibitors of metalloproteinases system, leading to change of structure of an extracellular matrix of a myocardium, are discussed.     

Distinct Spatio‐Temporal Extracellular Matrix Accumulation within Demyelinated Spinal Cord Lesions in Theiler's Murine Encephalomyelitis

The accumulation of extracellular matrix (ECM) and glial scar formation are considered important factors for the failure of regeneration in central nervous system (CNS) injury and multiple sclerosis. Theiler's murine encephalomyelitis (TME) as a model of multiple sclerosis served to evaluate the spatio‐temporal course of ECM alterations in demyelinating conditions. Microarray analysis revealed only mildly upregulated gene expression of ECM molecules, their biosynthesis pathways and pro‐fibrotic factors, while upregulation of matrix remodeling enzymes was more prominent. Immunohistochemistry demonstrated progressive accumulation of chondroitin sulfate proteoglycans, glycoproteins and collagens within demyelinated TME lesions, paralleling the development of astrogliosis. Deposition of collagen IV, laminin, perlecan and tenascin‐C started 28 days postinfection (dpi), collagen I, decorin, entactin and neurocan accumulated from 56 dpi on, and fibronectin from 98 dpi on. The basement membrane (BM) molecules collagen IV, entactin, fibronectin, laminin and perlecan showed perivascular and parenchymal deposition, while the non‐BM components collagen I, decorin, neurocan and tenascin‐C only accumulated in a nonvascular pattern in demyelinated areas. Contrary, phosphacan expression progressively decreased during TME. The immunoreactivity of aggrecan and brevican remained unchanged. The spatio‐temporal association of matrix accumulation with astrogliosis suggests a mainly astrocytic origin of ECM deposits, which in turn may contribute to remyelination failure in TME.     

不同频率张应变对大鼠血管平滑肌细胞外基质的影响

为研究不同频率张应变对血管平滑肌细胞(VSMC)细胞外基质(ECM)的影响,探讨不同频率张应变与血管重建(remodeling)的关系,本文应用 FX-4000TTM细胞应变加载系统,对体外培养的大鼠VSMC施加10%张应变,频率分别为0.5、1和2 Hz,加载时间为24 h,以未加载张应变的VSMC为对照组.采用Real-time RT-PCR、western blot等技术检测不同频率张应变对fibronectin、collagen I和collagen III表达的影响,以及可能参与调节的蛋白激酶p38的活性变化.结果显示:①张应变频率可以明显影响细胞外基质Fibronectin、collagen I和collagen III的mRNA的表达,其影响效果与频率大小是一种非线性关系;②蛋白激酶p38参与调节了一定频率张应变诱导的ECM的表达变化.结果表明不同频率的张应变可以影响VSMC细胞外基质表达的变化,提示频率的改变可能参与调节细胞外基质的合成与分泌;在应力引起的血管重建中频率的改变可能起着重要的作用.     

Extensive induction of important mediators of fibrosis and dystrophic calcification in desmin-deficient cardiomyopathy

Mice lacking the intermediate filament protein desmin demonstrate abnormal mitochondria behavior, disruption of muscle architecture, and myocardial degeneration with extensive calcium deposits and fibrosis. These abnormalities are associated with cardiomyocyte hypertrophy, cardiac chamber dilation and eventually with heart failure. In an effort to elucidate the molecular mechanisms leading to the observed pathogenesis, we have analyzed gene expression changes in cardiac tissue using differential display polymerase chain reaction and cDNA atlas array methods. The most substantial changes were found in genes coding the small extracellular matrix proteins osteopontin and decorin that are dramatically induced in the desmin-null myocardium. We further analyzed their expression pattern both at the RNA and protein levels and we compared their spatial expression with the onset of calcification. Extensive osteopontin localization is observed by immunohistochemistry in the desmin-null myocardium in areas with massive myocyte death, as well as in hypercellular regions with variable degrees of calcification and fibrosis. Osteopontin is consistently co-localized with calcified deposits, which progressively are transformed to psammoma bodies surrounded by decorin, especially in the right ventricle. These data together with the observed up-regulation of transforming growth factor-beta1 and angiotensin-converting enzyme, could explain the extensive fibrosis and dystrophic calcification observed in the heart of desmin-null mice, potentially crucial events leading to heart failure.