Sca-1 knockout impairs myocardial and cardiac progenitor cell function

Rationale: Cardiac progenitor cells are important for maintenance of myocardial structure and function, but molecular mechanisms governing these progenitor cells remain obscure and require elucidation to enhance regenerative therapeutic approaches. Objective: To understand consequences of stem cell antigen-1 (Sca-1) deletion on functional properties of c-kit+ cardiac progenitor cells and myocardial performance using a Sca-1 knock-out/green fluorescent protein knock-in reporter mouse (ScaKI). Methods and Results: Genetic deletion of Sca-1 results in early-onset cardiac contractile deficiency as determined by echocardiography and hemodynamics as well as age-associated hypertrophy. Resident cardiac progenitor cells in ScaKI mice do not respond to pathological damage in vivo, consistent with observations of impaired growth and survival of ScaKI cardiac progenitor cells in vitro. The molecular basis of the defect in ScaKI cardiac progenitor cells is associated with increased canonical Wnt signaling pathway activation consistent with molecular characteristics of lineage commitment. Conclusions: Genetic deletion of Sca-1 causes primary cardiac defects in myocardial contractility and repair consistent with impairment of resident cardiac progenitor cell proliferative capacity associated with altered canonical Wnt signaling.     

The in vitro response of phenotypically defined mouse stem cells and myeloerythroid progenitors to single or multiple growth factors.

Pluripotential stem cells (Thylo Lin- Sca+; referred to as Sca+) and primitive myeloerythroid progenitor cells (Thylo Lin- Sca-; referred to as Sca-), defined by their in vivo repopulating properties, have been purified from mouse bone marrow. In this study, the growth factor requirements of these two subsets were compared in colony-forming assays. Sca- progenitor cells grew well in interleukin (IL) 3 alone and showed maximum growth when two factors, IL-3 plus IL-1 or IL-3 plus IL-6, were combined. In contrast, Sca+ stem cells were generally not responsive to any single factor tested. Some colony formation was found when IL-3 was paired with either IL-1 or IL-6, and this was significantly enhanced as additional factors were included. A remarkable frequency of as much as 1 colony per 1.7 input Sca+ cells was achieved when IL-1, IL-3, IL-6, and colony-stimulating factors were used together. These differences in factor requirements presumably reflect the need for multiple factor signaling in the more primitive stem cell population. In most other aspects of colony formation, Sca+ and Sca- cells were very similar. They generated colonies that had equivalent distributions in size and cellular composition. One notable difference was found in the kinetics of their response. Whereas nearly all Sca- cells formed colonies within 7 days, a significant fraction of Sca+ cells delayed colony formation for greater than 1 week. During this quiescent period, cell survival was absolutely dependent on the presence of factors in the medium.     

大麻素Ⅱ型受体激动剂促进小鼠心肌梗死后心脏干／祖细胞增殖的作用

目的：探讨大麻素Ⅱ型受体（CB2）选择性激动剂AMl241对小鼠心肌梗死（MI）模型中心脏干／祖细胞增殖的作用。方法：40只雄性C57BL／6小鼠通过结扎小鼠心脏左冠状动脉前降支建立MI模型并随机分为4组,每组10只（n=10）：①假手术（Sham）组;②MI组;③MI＋CB：受体激动剂AMl241（MI＋AMl241）组;④MI＋CB2受体激动剂AMl241＋CB2受体拮抗剂AM630（MI＋AMl241＋AM630）组。采用小动物超声系统观察小鼠左室射血分数（LVEF）的变化。用免疫荧光染色法观察MI周边区表达干细胞生长因子受体（c-kit）、干细胞抗原1（Sea-1）的阳性细胞数,实时荧光定量PCR测定MI周边区c-kit、Sea-1和多药耐药蛋白P糖蛋白（MDRl）的表达水平。结果：与MI组相比,MI＋AMl241组小鼠7d和14d心脏LVEF值显著提高（P〈0．01）。免疫荧光染色的结果提示,MI＋AMl241组c-kit和Sea-1的表达较MI组增多（P〈0．05）。实时荧光定量PCR结果显示,MI＋AMl241组c-kit和Sea-1的基因表达水平明显高于MI组（P〈0．05）。同时,CB2受体拮抗剂AM630可阻断AMl241的上述作用。结论：CB2受体激活可促进梗死心肌干／祖细胞的增殖,改善心脏的收缩功能。     

C-kit+ CD45− cells found in the adult human heart represent a population of endothelial progenitor cells

Although numerous reports support the existence of stem cells in the adult heart, few studies have been conducted using human cardiac tissue. Therefore, cells from human cardiac atrial biopsies were analyzed regarding progenitor properties. Expression of stem cell markers was analyzed using fluorescence-activated cell sorting. This identified a small population of C-kit+ cells, which could be further subdivided based on expression of CD45. The C-kit+ CD45+ population was determined to be of mast cell identity, while the C-kit+ CD45− population expressed mRNA of the endothelial lineage. Since the number of cells obtainable from biopsies was limited, a comparison between directly isolated and monolayer and explant cultured cells, respectively, was carried out. While both cultures retained a small population of mast cells, only monolayer culture produced a stable and relatively high percentage of C-kit+ CD45− cells. This population was found to co-express endothelial progenitor cell markers such as CD31, CD34, CXCR4, and FLK-1. The mRNA expression profile was similar to the one from directly isolated cells. When sorted cells were cultured in endothelial differentiation medium, the C-kit+ CD45− population retained its expression of endothelial markers to a large extent, but downregulated progenitor markers, indicating further differentiation into endothelial cells. We have confirmed that the human cardiac atrium contains a small C-kit+ CD45− population expressing markers commonly found on endothelial progenitor cells. The existence of an endothelial progenitor population within the heart might have future implications for developing methods of inducing neovascularization after myocardial infarction.     

Hematopoietic stem cells and endothelial cell precursors express Tie-2, CD31 and CD45

Early theories of tumor angiogenesis suggested that preexisting vessels surrounding the tumor were the principal source of the tumor vasculature but recent evidence suggests that endothelial progenitor cells (EPC) migrate from the marrow play an important role in developing the tumor blood supply. In a mouse model, in which the vascularization of a transplantable tumor was studied after bone marrow (BM) transplantation, we show that cells that express Tie-2, Sca-1, CD31 and CD45 function as both BM EPC and primitive hematopoietic stem cells. BM cells from transgenic mice expressing green fluorescent protein (GFP) under the control of the endothelial lineage-specific Tie-2 promoter (Tie-2 /GFP) were used to reconstitute irradiated (12 Gy) wild-type mice. Five donor BM cell populations were studied: (1) whole BM; (2) Sca-1-enriched BMC; (3) GFP/Tie-2+, Sca-1+ BMC; (4) GFP/Tie-2-, Sca-1+ BMC and (5) Sca-1-depleted BMC. After 4 weeks, the mice were injected with Tg.AC tumor cells. Three weeks later, sections from the tumors were stained for CD31 and examined for Tie-2-driven GFP expression. BM-derived endothelial cells were found only in mice transplanted with bone marrow containing populations of Tie-2+, Sca-1+ cells. As few as 3500 of these cells were sufficient to radioprotect lethally irradiated mice. Thus, we conclude that a rare subset of BMC (approximately 4 x 10(-3)%) with the putative properties of hemangioblasts have an active Tie-2 promoter. Selection of Tie-2+Sca-1+ BMC enriches for marrow-derived EPCs that participate in tumor angiogenesis and cells that can provide hematopoietic reconstitution of marrow-ablated mice.     

Sca-1 expression is associated with decreased cardiomyogenic differentiation potential of skeletal muscle-derived adult primitive cells

Adult stem cells from skeletal muscle (SM) have been shown to differentiate into multiple lineages. The impact of stem cell antigen-1 (Sca-1) expression on cardiomyogenic differentiation potential of SM-derived primitive cells remains unknown. Cardiomyogenic differentiation was induced in freshly isolated or culture-expanded Sca-1+/CD45-/c-kit-/Thy-1+ (SM+) and Sca1-/CD45-/c-kit-/Thy-1+ (SM-) cells isolated from SM of C57BL/6 mice. Expression of mRNA of cardiac-specific antigens and those associated with pluripotency was examined by real-time RT-PCR. Phenotypic analysis of expanded cells was performed during each passage by flow cytometry. Cardiomyocytic differentiation in vitro was verified by morphologic analysis, immunocytochemistry, and contractile properties. In freshly isolated cells, compared with unfractionated SM-derived cells as well as SM+ cells, mRNA expression of cardiac-specific antigens and those associated with cellular pluripotency was greater in SM- cells. Compared with SM- cells, SM+ cells exhibited greater expansion capacity. Freshly isolated SM- cells exhibited greater cardiac differentiation potential compared with freshly isolated SM+ cells (21.8+/-0.3% of SM- cells positive for cardiac markers vs. 9.1+/-0.7% of SM+ cells, P=0.00009). Differentiated SM- cells acquired a cardiomyocytic phenotype and exhibited spontaneous rhythmic contractions in vitro. The number of Sca-1+ cells in the SM- population increased markedly with time (0.9+/-0.1% in freshly isolated cells vs. 11.9+/-0.9% after the first passage vs. 99.0+/-0.6% after the second passage). This increase in Sca-1 expression was associated with a marked decline in the expression of cardiac markers following differentiation induction in culture-expanded SM- cells (21.8+/-0.3% in unexpanded cells vs. 16.6+/-1.3% after the first passage vs. 6.0+/-0.5% after the second passage, P=0.00001 vs. unexpanded cells). In contrast, the SM+ cells did not exhibit any consistent pattern in either phenotypic or differentiation capability with expansion. We conclude that SM- cells are inherently predisposed to undergo cardiac differentiation and are enriched in markers of pluripotency. While both Sca-1+ and Sca-1- primitive cells from SM can undergo cardiac differentiation, Sca-1- cells exhibit greater cardiomyogenic potential, and the appearance of Sca-1 during expansion is associated with a decline in cardiac differentiation plasticity.     

TGF-β1 enhances cardiomyogenic differentiation of skeletal muscle-derived adult primitive cells

The optimal medium for cardiac differentiation of adult primitive cells remains to be established. We quantitatively compared the efficacy of IGF-1, dynorphin B, insulin, oxytocin, bFGF, and TGF-β1 in inducing cardiomyogenic differentiation. Adult mouse skeletal muscle-derived Sca1+/CD45-/c-kit-/Thy-1+ (SM+) and Sca1-/CD45-/c-kit-/Thy-1+ (SM-) cells were cultured in basic medium (BM; DMEM, FBS, IGF-1, dynorphin B) alone and BM supplemented with insulin, oxytocin, bFGF, or TGF-β1. Cardiac differentiation was evaluated by the expression of cardiac-specific markers at the mRNA (qRT-PCR) and protein (immunocytochemistry) levels. BM+TGF-β1 upregulated mRNA expression of Nkx2.5 and GATA-4 after 4 days and Myl2 after 9 days. After 30 days, BM+TGF-β1 induced the greatest extent of cardiac differentiation (by morphology and expression of cardiac markers) in SM- cells. We conclude that TGF-β1 enhances cardiomyogenic differentiation in skeletal muscle-derived adult primitive cells. This strategy may be utilized to induce cardiac differentiation as well as to examine the cardiomyogenic potential of adult tissue-derived stem/progenitor cells. Electronic supplementary material  The online version of this article (DOI:) contains supplementary material, which is available to authorized users. Returned for 1. Revision: 8 January 2008 1. Revision received: 8 April 2008 Ahmed Abdel-Latif and Ewa K. Zuba-Surma contributed equally to this work.     

Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I^(neg) and MHC I^(pos) cells were separated by magnetic cell sorting. The MHC I^(neg) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I^(neg) and ^(pos) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I^(neg) cells showed reduced cell death and leukocyte proliferation compared to MHC I^(pos) cells. MHC I^(neg) and ^(pos) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I^(neg) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I^(neg) cells preserved cardiac function, decreased infarct size and improved regeneration post–MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine.     

Sca-1~+心肌干细胞的研究进展

干细胞抗原1(Sca-1)是干细胞的一种重要表面标记物,体内许多干细胞都表达Sca-1。同样,心肌干细胞也表达Sca-1。目前研究发现,Sca-1+心肌干细胞能够分化为心肌细胞,对心肌梗死后心室重构与心肌再生具有明显作用,能够促进心脏的修复。因此,Sca-1+心肌干细胞有可能使心肌梗死的临床治疗取得实质性的进展。现综述了Sca-1+心肌干细胞的来源、分化、作用等方面。     

SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells

Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.     

Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo

Axin proteins are key negative regulators of the canonical Wnt signal transduction pathway. Although Axin2 null mice are viable, we identified an unusual ENU-induced recessive allele of Axin2, canp, that causes midgestation lethality in homozygotes. We show that the Axin2(canp) mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2(canp) protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2(canp) mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2(canp) mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2(canp) mutant embryos that is associated with the formation of an ectopic tail in some mutants. Treatment of wild-type embryos with an inhibitor of Tankyrase that stabilizes Axin proteins also causes inhibition of Wnt signaling in anterior regions of the embryo and a gain of Wnt signaling in the primitive streak. The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak.     

Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction

The adult bone marrow (BM) harbors Sca-1+/Lin−/CD45− pluripotent very small embryonic-like stem cells (VSELs), which can differentiate in vitro into several lineages, including cardiac and vascular lineages. Since mobilization of stem/progenitors from the BM is a prerequisite for their participation in organ repair, we investigated whether VSELs are mobilized into the peripheral blood (PB) after acute myocardial infarction (MI). Wild-type mice (C57BL/6 strain, 6- or 15-wk-old) underwent a 30-min coronary occlusion followed by reperfusion (groups III-V, VIII-X, n = 6-12/group) or a 1-hour open-chest state (sham controls, groups II and VII, n = 8-12/group); mice were sacrificed 24 h, 48 h, or 7 days later and PB samples were harvested. Controls (groups I and VI, n = 6/group) were sacrificed without any intervention. By flow cytometry, VSELs were barely detectable in PB under baseline conditions but their levels increased significantly at 48 h after MI, both in younger (6-wk-old) and older (15-wk-old) mice (3.33 ± 0.37 and 7.10 ± 0.89 cells/µl of blood, respectively). At 48 h after MI, qRT-PCR analysis revealed significantly increased levels of mRNA of markers of pluripotency (Oct-4, Nanog, Rex-1, Rif1, and Dppa1) in PB cells of 6-wk-old (but not 15-wk-old) infarcted mice compared with either controls or sham controls. Confocal microscopy and ImageStream analysis confirmed that mobilized VSELs expressed Oct-4 protein, while Sca-1+/Lin−/CD45+ hematopoietic stem cells did not. This is the first demonstration that Oct-4+ pluripotent stem cells (VSELs) are mobilized from the BM into the PB after acute MI. This phenomenon may have pathophysiological and therapeutic implications for repair of infarcted myocardium.     

Parathyroid hormone treatment after myocardial infarction promotes cardiac repair by enhanced neovascularization and cell survival

AIMS: An ongoing concept is that stem cells have the potential to regenerate the injured myocardium. In addition to direct vasorelaxing effects on the vasculature, which are mediated by an increased cAMP production leading to a decreased calcium influx in smooth muscle cells, parathyroid hormone (PTH) was recently shown to facilitate stem cell mobilization. Therefore, we analysed in a murine model of experimental myocardial infarction (MI) the influence of PTH treatment on survival, functional parameters, stem cell migration, and expression of vascular endothelial growth factor A (VEGF-A). METHODS AND RESULTS: Mice (C57BL/6) were treated with PTH (80 microg/kg/d) for up to 14 days after coronary artery ligation. Functional and immunohistochemical analyses were performed at days 6 and 30 after MI. Stem cells and VEGF expression in the myocardium were analysed by FACS and qRT-PCR at day 2 after MI. PTH-treated animals revealed a significant improvement of post-MI survival and myocardial function that was related to a subsequent reduction of left ventricular wall thinning and scar extension. Infarcted hearts of PTH-treated mice revealed increased numbers of CD45(+)/CD34(+) progenitor cells as well as an upregulation of VEGF-A mRNA associated with increased neovascularization and cell survival. CONCLUSIONS: PTH application after MI increases migration of angiogenic CD45(+)/CD34(+) progenitor cells to the ischaemic heart, which may attenuate ischaemic cardiomyopathy. As PTH is already used in patients with osteoporosis, our findings may have a direct impact on the initiation of clinical studies in patients with ischaemic heart disease.     

Inflammation and postinfarct remodeling: overexpression of IkappaB prevents ventricular dilation via increasing TIMP levels

OBJECTIVE: Nuclear factor-kappa B (NF-kappaB) orchestrates genes involved in inflammation and extracellular matrix (ECM) remodeling following myocardial infarction (MI). The objective of the present study was to investigate the effect of overexpression and mode of function of IkappaB, the natural inhibitor of NF-kappaB, on ECM remodeling in a rat model of MI. METHODS: MI was induced in male Sprague-Dawley rats by ligation of the left anterior descending coronary artery (LAD) and was followed by adenovirus-mediated intramyocardial transfection of IkappaB (n = 26) or LacZ reporter genes (n = 26). Sham-operated animals (n = 14) served as controls. RESULTS: In transthoracic echocardiography 49 days after MI, systolic and diastolic left ventricular dimensions were reduced while fractional shortening was preserved in the treatment group. Additionally, evaluation on the isolated heart showed an attenuated downward shift of pressure-volume relationships in the IkappaB group compared to LacZ. NF-kappaB p65 DNA binding activity was diminished both at 5 and 49 days post-MI in the treatment group. Five days post-MI in the treatment group, protein levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were significantly reduced by 72.6% and 73.2%, respectively, compared to LacZ (p<0.05). In parallel, matrix metalloproteinase (MMP)-2 and MMP-9 levels were reduced 5 days post-MI, with MMP-9 still being decreased 49 days post-MI (p<0.01). In contrast, tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 were increased compared to LacZ (p<0.01 and p<0.05, respectively) 5 days post-MI. After 49 days, TIMP-2, -3, and -4 expressions were significantly elevated (p<0.05). CONCLUSION: Reducing NF-kappaB activity via IkappaB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and -9 levels while increasing TIMP-1, -2, -3, and -4 levels. Therefore, IkappaB overexpression prevents ventricular dilation and consequently preserves cardiac function.     

Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment

BACKGROUND: Transplantation of bone marrow derived adult stem cells (BMC) improves cardiac function after acute myocardial infarction (MI). However, the cell population mediating myocardial recovery and the fate of the transplanted cells are still controversial. AIMS: We determined the effects of Sca-1+ c-kit+ lin- haematopoietic BMC on cardiac function after MI and the cell fate after transplantation. METHODS: Sca-1+ c-kit+ lin- BMC of male donor C57BL/6 mice were transplanted by intravenous injection into syngenic females after permanent MI. LV dimensions and function were determined by echocardiography and cardiac magnetic resonance imaging, transplanted BMC were identified by Y chromosome DNA in situ hybridization. RESULTS: BMC treatment completely prevented LV dilation (LV end-diastolic volume BMC 70 +/- 16 microl vs. control 122 +/- 41 microl; p < 0.05) and improved fractional shortening (BMC 22.9 +/- 8% vs. control 15.4 +/- 8.4%; p < 0.05) and ejection fraction BMC 68.2 +/- 6.6% vs. control 52 +/- 14.3%; p < 0.05) as early as 3 days after transplantation, but did not decrease infarct size (BMC 27 +/- 6% vs. control 28 +/- 7%, p = n.s.). After 4 weeks, only sporadic cells of male origin were identified in infarcted hearts (< 0.01% of periinfarct cells). CONCLUSION: Intravenous injection of Sca-1+ c-kit+ lin- in BMC after MI improves LV dimensions and function without evidence for long term engraftment.     

Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction

Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.     

Osteopontin: Role in extracellular matrix deposition and myocardial remodeling post-MI

Remodeling after myocardial infarction (MI) associates with left ventricular (LV) dilation, decreased cardiac function and increased mortality. The dynamic synthesis and breakdown of extracellular matrix (ECM) proteins play a significant role in myocardial remodeling post-MI. Expression of osteopontin (OPN) increases in the heart post-MI. Evidence has been provided that lack of OPN induces LV dilation which associates with decreased collagen synthesis and deposition. Inhibition of matrix metalloproteinases, key players in ECM remodeling process post-MI, increased ECM deposition (fibrosis) and improved LV function in mice lacking OPN after MI. This review summarizes — 1) signaling pathways leading to increased expression of OPN in the heart; 2) the alterations in the structure and function of the heart post-MI in mice lacking OPN; and 3) mechanisms involved in OPN-mediated ECM remodeling post-MI.