Published online before print June 14, 2007, doi: 10.1161/CIRCRESAHA.107.149047
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© 2007 American Heart Association, Inc.
Integrative Physiology |
Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling
From the Department of Pediatrics (T.O., J.X., R.A.K., J.M., M.H., M.A.S., A.L., E.W.B., G.W.D., B.J.A., J.R., J.D.M.), University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Ohio; Department of Medicine (E.W.B., G.W.D.), University of Cincinnati, Ohio; and Cardiovascular Development Group (S.J.C.), Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis.
Correspondence to Jeffery D. Molkentin, Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}cchmc.org
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Abstract |
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The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn–/– mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn–/– hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn–/– hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.
Key Words: cardiac • signaling • hypertrophy • remodeling • mouse genetics
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Introduction |
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Heart disease remains among the most prevalent and lethal diseases in the western world, with heart failure representing the fastest growing subclass of disease that presently afflicts nearly 5 million Americans.1–3 One common characteristic that underlies nearly all forms of heart failure is a remodeling of the extracellular matrix (ECM) and an associated change in ventricular geometry.4,5 For example, dilated cardiomyopathy is characterized by a thinning of the ventricular walls that likely results, in part, from a "loosening" of the ECM within the heart, whereas a restrictive cardiomyopathy is often associated with an increase in ventricular stiffness, an overabundance of fibrosis, and inappropriate ECM expansion.4,5 These heart failure–associated alterations in the cardiac ECM are likely regulated, in part, by the cardiac fibroblast through both stretch-sensitive signaling pathways and by neuroendocrine effectors such as angiotensin II and transforming growth factor (TGF)ß.6,7 In response to disease stimuli that are associated with ventricular remodeling and heart failure, the activity of myocardial fibroblasts and the molecular composition of the ECM becomes altered.6,7 For example, pressure overload and myocardial infarction (MI) in both rodents and humans is associated with a dramatic reexpression of the ECM protein periostin (Pn).8–11
Pn is a 90-kDa secreted protein involved in cell adhesion but otherwise of relatively unknown function.12,13 Pn contains 4 repetitive fasciclin domains that are similar in sequence to the insect protein fasciclin I, which is involved in neuronal cell–cell adhesion.14 Pn is related to another secreted fasciclin-domain-containing protein ßIG-H3, which like Pn is expressed in collagen-rich connective tissues or remodeling centers, and is induced by TGFß.13,15 Pn shows a dynamic expression profile, both developmentally and in adult tissues that are undergoing remodeling or active stress. Pn is expressed in the developing endocardial cushions of the heart and the mature valves,16 the periosteum and periodontal ligament,13 injured vessels,17 tumors and metastatic cancer cells,18 and in cells undergoing mesenchymal transformation.18,19 With respect to cell type of expression, Pn appears to be expressed exclusively in fibroblasts, or in cells that adopt fibroblast-like characteristics following an injury event.16,20–22 As a secreted ECM protein that associates with areas of fibrosis, Pn can directly interact with other ECM proteins such as fibronectin, tenascin-C, collagen I, collagen V, and heparin.22–25 Pn serves as a ligand for select integrins, such as 
Vß3, Vß5, and 4ß6, where it can affect the ability of cells (fibroblasts or cancer cells) to migrate and/or undergo a mesenchymal transformation in select tissues.18,19,26,27
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Materials and Methods |
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For an expanded Materials and Methods, see the online data supplement available at http://circres.ahajournals.org. Pn–/– (Postn gene) mice were generated by gene targeting in embryonic stem cells, whereas PntTA-inducible transgenic mice were generated using a tetracycline-regulated system based on the
-myosin heavy chain promoter.28 Procedures for echocardiography in mice were described previously,29 as were procedures for pressure overload by transverse aortic constriction (TAC) in mice30 and MI in mice.29 Western blotting for cardiac proteins and the processing of cardiac extracts was performed as described previously.29 Determination of cardiac collagen content by analysis of hydroxyproline content was also described previously.31 The myeloperoxidase assay for granulocyte content in the heart was performed as described previously.32 |
Results |
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Generation of Pn–/– Mice and PntTA-Inducible Transgenic Mice
To begin to understand the functional role of Pn reexpression in the heart, we generated Pn–/– mice by targeting the Postn gene in embryonic stem cells, replacing exons 4 to 10 encoding three of the 4 fasciclin domains, which produced a null allele (Figure 1A). Indeed, analysis of Pn protein expression in the developing feet (sites of high Pn expression) or hearts of 1-day-old mice showed no expression in Pn–/– compared with wild types (Figure 1B). No significant Pn protein was found within the ECM of the heart after postnatal development, although the valves show persistent expression within fibroblasts (data not shown).
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Pn overexpressing transgenic mice were also generated to investigate the biologic effect normally associated with induced expression in the heart. A modified -myosin heavy chain promoter was used as the responder transgene,28 which when crossed with transgenic mice containing the -myosin heavy chain promoter driven tet-transactivator (tTA) protein, produces cardiac-specific expression that can be regulated, although only constitutive expression was used throughout this study (Figure 1C). Although Pn expression is normally exclusive to fibroblasts, its production in cardiac myocytes here served as a surrogate to achieve heart-specificity (see Figure 2C). Indeed, cardiomyocytes efficiently produced and released Pn into the ECM in a pattern that was identical to endogenous production after stress stimulation from fibroblasts. Four independent lines of PntTA-containing mice were initially characterized with robust expression, but only one line is shown given a similar overall phenotype (Figure 1D). The level of Pn overexpression in this line is approximately 5- to 6-fold greater than is normally observed in the heart following MI or pressure overload (data not shown).
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The majority of Pn–/– mice survived well into adulthood but showed smaller overall body weights (Figure 1E) and no alteration in ventricular weight normalized to body weight (Figure 1F). Deletion of Pn by 2 other groups also revealed a similar phenotype, as well as defective tooth development and an approximate 14% neonatal lethality.25,33 Otherwise, Pn–/– mice appeared relatively normal with no alterations in cardiac morphology or ventricular performance, although hearts were slightly smaller (Figure I and Table I in the online data supplement). PntTA transgenic mice were also unaffected as young adults and showed normal heart morphology, ventricular performance, and a lack of fibrosis (Figure 1G; supplemental Figure I and Table II). However, by 24 weeks of age, they showed signs of hypertrophy by echocardiography, which produced a significant increase in ventricular weight normalized to body weight by 32 weeks of age (Figure 1G and supplemental Table II). Despite the hypertrophy, PntTA transgenic mice maintained normal ventricular performance up to 36 weeks of age, suggesting that Pn overexpression did not lead to decompensation.
Pn Is Reexpressed in Cardiac Fibroblasts Following Injury
Western blotting from adult hearts showed reexpression of Pn protein following pressure overload induced by TAC for 1 day, 1 week, 2 weeks, and 8 weeks, whereas no protein was observed in the ventricles of sham-operated adult mice (Figure 2A and 2B). Immunohistochemical analysis of Pn protein in the ventricles showed no expression in sham mice but abundant accumulation within the interstitial space after 8 weeks of TAC in wild-type hearts (mice were 14 to 16 weeks of age) (Figure 2C). The same pattern of interstitial localization of Pn protein was observed in unstressed PntTA transgenic mice (10 weeks of age) (Figure 2C). Pn protein reexpression was also observed in the ventricles by 4 days after a MI and then maintained thereafter up to 8 weeks of age (Figure 2D and 2E). Interestingly, Pn protein appears to persist for a number of weeks after an injury event, even after mRNA induction is lost (data not shown). Also of interest, 2 protein isoforms of Pn are usually observed on induction in the heart, which may reflect differential splicing within the 23 exons comprising the gene (supplemental Figure II). The most abundant full-length 23-exon-containing form of Pn was used for transgenic overexpression. Immunohistochemical analysis 1 week after MI injury showed massive accumulation of Pn protein within the scar, as well as between myocytes in the ECM of the periinfarct region (Figure 2F). Interestingly, hypertrophy induced by forced swimming or voluntary wheel running exercise did not induce Pn protein expression, despite a 25% and 16% hypertrophy response, respectively (Figure 2G).30 Thus, Pn protein reexpression is likely selective to pathological stimuli and is not involved in physiologic hypertrophy.
Finally, we also confirmed previous reports that Pn expression is exclusive to fibroblasts.16,20–22 Confocal microscopy for Pn and vimentin colocalization showed expression in fibroblasts within the ECM of the heart 7 days after MI (Figure 2H). A similar pattern of colocalization was also observed between Pn and DDR2, which is another fibroblast enriched marker (data not shown). There were no obvious differences in overall fibroblast numbers in the hearts of adult wild-type versus Pn–/– mice as assessed by vimentin immunohistochemistry at baseline, although after MI, Pn–/– hearts had significantly less of an increase in fibroblasts in the left ventricle (Figure 2I).
Analysis of MI-Mediated Rupture and Remodeling in Pn–/– Mice
Because Pn protein is reexpressed within the ECM following cardiac injury, we reasoned that it might affect the response. Indeed, Pn–/– mice showed a significant increase in death in the first 10 days after MI injury, associated with a 2-fold greater rate of ventricular wall rupture compared with strain-matched wild-type controls (P<0.05) (Figure 3A). However, Pn–/– mice that survived the initial scar formation phase maintained cardiac function better than wild types over the next 8 weeks (Figure 3B and supplemental Table III). Importantly, Pn–/– mice showed the same infarction area normalized to area-at-risk as wild-type mice 24 hours after ischemia/reperfusion injury (Figure 3C). The relative degree of fibrosis and the overall size of the scar itself were noticeably reduced in Pn–/– mice compared with wild-type mice, suggesting a reason underlying the improved functional profile of Pn–/– mice (Figure 3D). Indeed, Pn–/– mice also showed less inflammatory cell recruitment as assessed with a total tissue myeloperoxidase activity assay or a Western blot for a macrophage specific maker (CD68) following MI, consistent with the observed reduction in fibrosis and scar size (Figure 3E and 3F).
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Although loss of Pn was protective following in the later phases after an MI, overexpression of Pn showed no effect on these indices or the degree of functional deterioration (Figure 3G and supplemental Table III). Thus, increased Pn did not increase fibrosis or scar size following MI injury, suggesting that Pn secretion is not a rate-limiting aspect of the fibrotic response. However, none of the expired PntTA transgenic mice showed ventricular wall rupture compared with obvious examples of rupture in the wild-type controls. Thus, Pn overexpression appears to protect from myocardial wall rupture (see discussion).
Pn–/– Mice Have Preserved Function and Less Hypertrophy Following Pressure Overload
Because Pn is reexpressed fairly rapidly in pressure overloaded mouse hearts, we reasoned that it might modulate the ensuing disease response. Indeed, whereas the cardiac hypertrophic response was not different between Pn–/– mice and wild-type mice in the first 2 weeks of pressure overload, Pn–/– mice showed no progression or worsening of hypertrophy after 8 weeks, compared with significantly more hypertrophy in wild-type mice (Figure 4A). Pressure gradients across the aortic constriction were not different between Pn–/– and wild-type mice (68.51±3.82 mm Hg, n=16 versus 67.67±3.46 mm Hg, n=12, respectively). Conversely, PntTA transgenic mice showed significantly greater cardiac hypertrophy 8 weeks after pressure overload compared with wild-type controls of the same strain (Figure 4B). Once again, pressure gradients across the aortic constrictions were not different between PntTA and wild-type mice (data not shown). At the cellular level, cross-sectional areas of myocytes from ventricular histological sections were significantly smaller in Pn–/– mice compared with their respective controls, whereas cross-sectional areas were significantly larger in PntTA transgenic mice compared with FVB controls following 8 weeks of pressure overload (Figure 4C and 4D).
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Pn–/– mice also maintained ventricular performance better than wild-type mice at 3, 5, and 8 weeks of pressure overload, suggesting that loss of Pn protected the heart from decompensation (Figure 4E and supplemental Table IV). This functional improvement also correlated with significantly less collagen accumulation in the heart over 8 weeks in Pn–/– mice compared with wild-type mice (Figure 4G). However, overexpression of Pn did not enhance functional decompensation of the heart following 8 weeks of pressure overload, nor did it increase cardiac fibrosis, suggesting that it may not be a rate determining factor of fibrosis (Figure 4F and 4G; supplemental Table IV). It should also be noted that the FVB genetic background consistently showed little collagen accumulation following pressure overload, compared with the C57BL/6 strain background, the latter of which were also more susceptible to decompensation following cardiac injury (Figure 4G).
Altered Fibrotic Gene Program in Pn–/– Mouse Hearts
To begin to dissect the mechanistic underpinnings of the reduced fibrotic response in Pn–/– hearts following MI or long-term pressure overload, we used an Affymetrix gene arrays (Figure 5A). Pn–/– hearts at 8 weeks of age showed 449 genes with significantly altered expression compared with wild-type hearts of the same strain. Interestingly, a large set of these differentially expressed genes could be assigned to a biologic category involving fibrosis, cell adhesion, ECM, or that which are consistent with fibroblast function. For example, Pn–/– hearts showed dramatically reduced levels of collagen V3, although collagen I and collagen III were expressed normally in the adult heart of those animals that survived neonatal development (Figure 5B and 5C). Indeed, Pn–/– hearts showed significantly less collagen V accumulation in the heart following MI or TAC compared with wild-type hearts (Figure 5D and 5E).
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The difference in gene expression in Pn–/– hearts discussed above suggested an alteration in fibroblast function. To address this issue, we generated fibroblast cultures from wild-type and Pn–/– adult hearts for in vitro analysis. Fibroblast proliferation rates assessed by [3H]-thymidine incorporation or immunocytochemistry for phosphorylated histone H3 did not vary between wild-type and Pn–/– fibroblasts (Figure 6A and 6B). Consistent with these observations, increased expression of Pn using a recombinant adenovirus also did not alter proliferation rates in wild type of Pn–/– fibroblast cultures (Figure 6C). There was also no difference in the percentage of myofibroblasts induced at low culture densities as quantified by staining for smooth muscle -actin between wild-type and Pn–/– fibroblasts (Figure 6D). However, Pn–/– fibroblasts showed dramatically different adhesive properties. For example, at 4, 8, 16, and 48 hours, fewer neonatal cardiomyocytes attached to Pn–/– fibroblasts compared with wild-type fibroblasts (Figure 7A and 7B). The use of a mouse–rat coculturing system between fibroblasts and cardiomyocytes has been described previously.34 The reciprocal experiment was also performed in which a lawn of neonatal cardiomyocytes was used to quantify the attachment of wild-type or Pn–/– fibroblasts at 1 and 3 hours, and the results showed a similar defect in Pn–/– fibroblasts (Figure 7C). Interestingly, addition or restoration of Pn protein in wild-type and Pn–/– fibroblasts, respectively, did not enhance adhesion in either cell culture assay (Figure 7C and data not shown). These results suggested that Pn–/– fibroblasts might be inherently different based on their development in the absence of Pn protein. Indeed, we performed an Affymetrix array for global gene expression changes from cardiac fibroblasts isolated at 6 weeks of age from wild-type and Pn–/– mice. The results showed a significant change in approximately 7% of all expressed genes (data not shown).
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Discussion |
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Here we observed that Pn contributes to the cardiac hypertrophic response, an observation that was not anticipated, given its primary function as an ECM cellular adhesion protein. That a cellular adhesion protein might affect the cardiac hypertrophic response is not without precedence, especially given the known importance of integrins in regulating cardiac reactive signaling4,35 and given the known role of Pn as a substrate for multiple combinations of integrins. For example, both focal adhesion kinase and integrin-linked kinase, which are intracellular signaling components of the integrin complex, function as important regulators of the cardiac hypertrophy response.36,37 Indeed, mice lacking the protein osteopontin, which is another cardiac inducible and secreted ECM protein that binds integrins, showed less pressure overload hypertrophy compared with wild-type mice.38 Based on these results, it is tempting to speculate that Pn alters the cardiac hypertrophic response by affecting signaling within cardiac myocytes and fibroblasts through alterations in their engagement of integrins or other fasciclin domain containing proteins (membrane bound versions). The lack of Pn in the developing heart also appears to dramatically alter the molecular program within fibroblasts themselves, so that adult Pn–/– fibroblasts show dramatic changes in gene expression (7% of all genes). This inherent alteration in fibroblasts in Pn–/– hearts might also impact the hypertrophic response.
In addition to altering the hypertrophic response, loss of Pn compromised the fibrotic response of the heart following pressure overload stimulation and MI. This reduction in fibrosis initially promoted greater ventricular rupture following MI, although long term, it improved cardiac function in the surviving animals. The mechanism for increased rupture is reminiscent of corticosteroids and anti-inflammatory treatment regimens used in humans to reduce fibrosis following MI, but with the secondary consequence of increasing rupture rates.39 Even more germane, mice null for the angiotensin II type 2 receptor were characterized by significantly less fibrosis following MI injury, and a 63% death incidence attributable to rupture in the first 7 days, compared with a rate of 24% in wild-type mice.40 These results suggest that although inhibition of cardiac fibrosis benefits the long-term remodeling process and preserves cardiac function to a greater extent, in the short term, it can predispose to rupture by compromising scar formation.
Two other groups have previously attempted to manipulate expression of Pn or an alternately spliced isoform of Pn in the heart.10,21 Katsuragi et al attempted to overexpress Pn in the rat heart by transfection of a plasmid mixed with liposomes coated with the hemagglutinating virus of Japan.21 This same group attempted to knockdown Pn expression with a 1-time infusion of antisense oligonucleotides into the rat heart, after which function was assessed 43 days later.21 The main concern with this prior study was that protein expression afforded by either manipulation was not examined. In another study, Litvin et al injected an adenovirus encoding an alternatively spliced isoform of Pn into the heart, referred to as periostin-like factor (PLF), which after 7 days, caused no dilation but instead produced a minor increase in cardiac hypertrophy.10 However, our PntTA transgenic mice did not show cardiac hypertrophy until 6 to 8 months of age, with sustained overexpression, suggesting that the viral infection protocol may have had a secondary influence in the study by Litvin et al or that the alternately spliced isoform functioned differently.
Our observations indicate that Pn itself does not nucleate the fibrotic response and that it is not a limiting component in the pathway to fibrotic deposition. However, loss of Pn compromised the efficiency of fibrosis development and ventricular remodeling, collectively suggesting that Pn is necessary but not sufficient in the remodeling and fibrotic response. Another consideration is that although Pn overexpression did not alter cardiac fibrosis, it still enhanced the cardiac hypertrophic response and protected hearts from rupture. We believe that the mechanistic role of Pn in altering the hypertrophy response is distinct from its potentially more passive role in affecting the fibrotic response (see below).
The alterations in cardiac remodeling and hypertrophy associated with Pn deletion are hypothesized to arise by 2 mechanisms. Pn might simply regulate the integrity of the ECM through its ability to bind multiple ECM proteins, such as tenascin-C, fibronectin, collagen V, collagen I, and heparin,22–25 thus affecting collagen synthesis and maturation through a complex series of architectural interactions. Indeed, as part of a collaborative study, we determined that collagen fibrils from Pn–/– mice were reduced in size, slightly disorganized, and less efficiently cross-linked.23 Thus, by regulating the integrity or composition of the ECM, Pn could alter the hypertrophic response by simply modifying the stretch characteristics of the tissue, impacting signaling as an indirect consequence. Another aspect of this passive regulation is that Pn appears to be a more-pliable substrate compared with fibronectin and vitronectin, possibly affecting how mesenchymal cells (fibroblasts, inflammatory cells, stem cells) migrate within the heart following injury.18 Indeed, transformed cells preferentially secrete Pn to facilitate invasiveness and metastatic activity.18,26,27 This same static feature of ECM pliability may also underlie invasiveness of mesenchymal cells into endocardial cushions in the presence of Pn in the developing heart.19
A second possibility is that Pn is a more-active participant in the remodeling and hypertrophic response by altering the phenotype of fibroblasts and/or cardiomyocytes through attachment-dependent signaling (which could also be an epigenetic developmental effect that is maintained in adulthood). Pn supports vß5 integrin signaling to facilitate epithelial–mesenchymal transition and metastatic activity,18,27 as well as for movement of cells in the developing bone centers or periodontal ligaments.20,25,33 In the same manner, Pn secretion in the heart might alter the movement or adherence of fibroblasts or inflammatory cells into areas of injured myocardium, where Pn is abundantly expressed and secreted.8–11
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Acknowledgments |
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Sources of Funding
This work was supported by the NIH (to J.D.M., G.W.D., and J.R.) and an international grant in heart failure research from the Fondation Leducq (to J.D.M.). J.D.M. is an Established Investigator of the American Heart Association.
Disclosures
None.
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Footnotes |
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*Both authors contributed equally to this work.
Original received January 20, 2007; revision received June 6, 2007; accepted June 6, 2007.
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