Simultaneous Transforming Growth Factor β-Tumor Necrosis Factor Activation and Cross-talk Cause Aberrant Remodeling Response and Myocardial Fibrosis in Timp3-deficient Heart

The pleiotropic cytokines, transforming growth factor β1 (TGFβ1), and tumor necrosis factor (TNF) play critical roles in tissue homeostasis in response to injury and are implicated in multiple human diseases and cancer. We reported that the loss of Timp3 (tissue inhibitor of metalloproteinase 3) leads to abnormal TNF signaling and cardiovascular function. Here we show that parallel deregulation of TGFβ1 and TNF signaling in Timp3−/− mice amplifies their cross-talk at the onset of cardiac response to mechanical stress (pressure overload), resulting in fibrosis and early heart failure. Microarray analysis showed a distinct gene expression profile in Timp3−/− hearts, highlighting activation of TGFβ1 signaling as a potential mechanism underlying fibrosis. Neonatal cardiomyocyte-cardiofibroblast co-cultures were established to measure fibrogenic response to agonists known to be induced following mechanical stress in vivo. A stronger response occurred in neonatal Timp3−/− co-cultures, as determined by increased Smad signaling and collagen expression, due to increased TNF processing and precocious proteolytic maturation of TGFβ1 to its active form. The relationship between TGFβ1 and TNF was dissected using genetic and pharmacological manipulations. Timp3−/−/Tnf−/− mice had lower TGFβ1 than Timp3−/−, and anti-TGFβ1 antibody (1D11) negated the abnormal TNF response, indicating their reciprocal stimulatory effects, with each manipulation abolishing fibrosis and improving heart function. Thus, TIMP3 is a common innate regulator of TGFβ1 and TNF in tissue response to injury. The matrix-bound TIMP3 balances the anti-inflammatory and proinflammatory processes toward constructive tissue remodeling. The pleiotropic cytokines, transforming growth factor β1 (TGFβ1), and tumor necrosis factor (TNF) play critical roles in tissue homeostasis in response to injury and are implicated in multiple human diseases and cancer. We reported that the loss of Timp3 (tissue inhibitor of metalloproteinase 3) leads to abnormal TNF signaling and cardiovascular function. Here we show that parallel deregulation of TGFβ1 and TNF signaling in Timp3−/− mice amplifies their cross-talk at the onset of cardiac response to mechanical stress (pressure overload), resulting in fibrosis and early heart failure. Microarray analysis showed a distinct gene expression profile in Timp3−/− hearts, highlighting activation of TGFβ1 signaling as a potential mechanism underlying fibrosis. Neonatal cardiomyocyte-cardiofibroblast co-cultures were established to measure fibrogenic response to agonists known to be induced following mechanical stress in vivo. A stronger response occurred in neonatal Timp3−/− co-cultures, as determined by increased Smad signaling and collagen expression, due to increased TNF processing and precocious proteolytic maturation of TGFβ1 to its active form. The relationship between TGFβ1 and TNF was dissected using genetic and pharmacological manipulations. Timp3−/−/Tnf−/− mice had lower TGFβ1 than Timp3−/−, and anti-TGFβ1 antibody (1D11) negated the abnormal TNF response, indicating their reciprocal stimulatory effects, with each manipulation abolishing fibrosis and improving heart function. Thus, TIMP3 is a common innate regulator of TGFβ1 and TNF in tissue response to injury. The matrix-bound TIMP3 balances the anti-inflammatory and proinflammatory processes toward constructive tissue remodeling. Tissue repair requires the coordinated response between cellular and stromal compartments, involving regulated cytokine release, inflammation, cellular turnover, and structural remodeling, in order to restore organ function. The consequence of an inadequate remodeling program is reflected as necrosis, hyperplasia, and fibrosis, which are the hallmarks of multiple human diseases. Tissue fibrosis is the outcome of excessive and disorganized deposition of extracellular matrix (ECM) 3The abbreviations used are: ECMextracellular matrixAng IIangiotensin IIPEphenylephrineTGFβtransforming growth factor βTNFtumor necrosis factorMMPmatrix metalloproteinaseABaortic bandingWTwild typePSRPicro-Sirius RedELISAenzyme-linked immunosorbent assayCTcycle thresholdqPCRquantitative PCR. 3The abbreviations used are: ECMextracellular matrixAng IIangiotensin IIPEphenylephrineTGFβtransforming growth factor βTNFtumor necrosis factorMMPmatrix metalloproteinaseABaortic bandingWTwild typePSRPicro-Sirius RedELISAenzyme-linked immunosorbent assayCTcycle thresholdqPCRquantitative PCR. proteins, resulting in disruption of normal tissue architecture and homeostasis that contributes to organ dysfunction. Myocardial fibrosis is the underlying cause of diastolic heart failure and a complicating factor in multiple heart disorders (1Zile M.R. Baicu C.F. Gaasch W.H. N. Engl. J. Med. 2004; 350: 1953-1959Crossref PubMed Scopus (1179) Google Scholar, 2Katz A.M. Zile M.R. Circulation. 2006; 113: 1922-1925Crossref PubMed Scopus (81) Google Scholar, 3Herpel E. Pritsch M. Koch A. Dengler T.J. Schirmacher P. Schnabel P.A. Histopathology. 2006; 48: 736-747Crossref PubMed Scopus (56) Google Scholar). Although cell surface-bound and soluble matrix metalloproteinases (MMPs) along with their natural tissue inhibitors (tissue inhibitors of metalloproteinase) constitute an important system for regulating ECM turnover (4Spinale F.G. Physiol. Rev. 2007; 87: 1285-1342Crossref PubMed Scopus (892) Google Scholar), inflammation is emerging as an important co-contributor to fibrosis (5Stramer B.M. Mori R. Martin P. J. Invest. Dermatol. 2007; 127: 1009-1017Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 6Sugimoto H. Grahovac G. Zeisberg M. Kalluri R. Diabetes. 2007; 56: 1825-1833Crossref PubMed Scopus (183) Google Scholar). Recent studies have linked specific subsets of metalloproteinases to inflammatory processes through their ability to cleave a wide variety of ECM-bound and cell surface cytokines (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 8Murphy G. Murthy A. Khokha R. Trends Immunol. 2008; 29: 75-82Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Common regulators of inflammatory cytokines and fibrogenic ligands may be the key to building an adequate tissue response, and their identification can lead to developing new strategies against tissue fibrosis.TGFβ1 is considered the major regulator of fibroblast response during normal ECM homeostasis as well as during the pathogenesis of fibrosis (9Gauldie J. Bonniaud P. Sime P. Ask K. Kolb M. Biochem. Soc. Trans. 2007; 35: 661-664Crossref PubMed Scopus (153) Google Scholar). TGFβ1-activated fibroblasts, characterized by the expression of α-smooth muscle actin, are the main source of collagen biosynthesis in the myocardium (10Stawowy P. Kallisch H. Veinot J.P. Kilimnik A. Prichett W. Goetze S. Seidah N.G. Chrétien M. Fleck E. Graf K. Circulation. 2004; 109: 770-776Crossref PubMed Scopus (32) Google Scholar). TGFβ1 can trigger the differentiation of cardiac fibroblasts to activated myofibroblasts that synthesize collagen types I and III (11Petrov V.V. Fagard R.H. Lijnen P.J. Hypertension. 2002; 39: 258-263Crossref PubMed Scopus (339) Google Scholar, 12Asano Y. Ihn H. Yamane K. Kubo M. Tamaki K. J. Clin. Invest. 2004; 113: 253-264Crossref PubMed Scopus (196) Google Scholar). It also regulates the proteolytic systems responsible for ECM turnover (13Overall C.M. Wrana J.L. Sodek J. J. Biol. Chem. 1991; 266: 14064-14071Abstract Full Text PDF PubMed Google Scholar). Secreted TGFβ1 is sequestered and concentrated in the ECM by specific binding proteins, which render it biologically inactive (14Hyytiäinen M. Penttinen C. Keski-Oja J. Crit. Rev. Clin. Lab. Sci. 2004; 41: 233-264Crossref PubMed Scopus (272) Google Scholar). Enhanced TGFβ1 signaling can result from defective matrix-binding due to fibrillin mutations as observed in Marfan syndrome or by increased release from the ECM through excessive proteolysis (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 15Mu D. Cambier S. Fjellbirkeland L. Baron J.L. Munger J.S. Kawakatsu H. Sheppard D. Broaddus V.C. Nishimura S.L. J. Cell Biol. 2002; 157: 493-507Crossref PubMed Scopus (584) Google Scholar, 16Jenkins G. Int. J. Biochem. Cell Biol. 2008; 40: 1068-1078Crossref PubMed Scopus (242) Google Scholar). As such, MMP2, -9, and -14 have been suggested to activate latent TGFβ1 directly, via cleavage and release of latency-associated peptide (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 15Mu D. Cambier S. Fjellbirkeland L. Baron J.L. Munger J.S. Kawakatsu H. Sheppard D. Broaddus V.C. Nishimura S.L. J. Cell Biol. 2002; 157: 493-507Crossref PubMed Scopus (584) Google Scholar). MMPs and TGFβ1 also play a role in fibroblast migration (17Stawowy P. Margeta C. Kallisch H. Seidah N.G. Chrétien M. Fleck E. Graf K. Cardiovasc. Res. 2004; 63: 87-97Crossref PubMed Scopus (97) Google Scholar). Altogether, and TGFβ1 may at to tissue fibrosis.TGFβ1 and TNF are cytokines, and each the activated by the cytokine Y. S. S. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. D. A. M. Genes Dev. 2000; 14: Google Scholar). fibrosis, for a that can or collagen to the response J. J. Physiol. 2007; PubMed Scopus Google Scholar). TNF been to TGFβ1 signaling through its which the 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, C. J. Invest. Dermatol. 2007; 127: Full Text Full Text PDF PubMed Scopus Google Scholar), of cross-talk between TGFβ1 and TNF as to ECM and cell G. Murthy A. Khokha R. Trends Immunol. 2008; 29: 75-82Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, M. Penttinen C. Keski-Oja J. Crit. Rev. Clin. Lab. Sci. 2004; 41: 233-264Crossref PubMed Scopus (272) Google Scholar). of the proteolytic cleavage of TNF the cell surface and of TGFβ1 to the to soluble an adequate of is critical for a coordinated cellular stress response, which in their extracellular mice have an abnormal inflammatory response due to excessive TNF signaling J.L. Khokha R. 2004; PubMed Scopus Google Scholar, Khokha R. J. Immunol. 2006; PubMed Scopus Google Scholar). Timp3−/− are to mechanical stress induced by of the and with an early onset of heart due to increased and metalloproteinase TNF processing and ECM Khokha R. Res. PubMed Scopus Google Scholar). Here we show that Timp3−/− as well as mice fibrosis a to the role of cytokine signaling in fibrosis. a neonatal cardiomyocyte-cardiofibroblast and genetic and pharmacological in we the of and the ability of TIMP3 to cytokines in the is a well established to cardiac the in with or tissue a coordinated response between cellular and stromal through the of cytokines that are regulated in and We show that TIMP3 is a common stromal regulator of critical proinflammatory (TNF) and anti-inflammatory cytokines in and its loss a distinct gene expression program The of cytokines at the of expression and maturation involving proteolytic to their as through the activation of their in TIMP3 reciprocal an cross-talk responsible for the tissue remodeling, which in fibrosis, and heart to in gene expression suggested an early of TGFβ1 in Timp3−/− mice the that TGFβ1 is responsible for fibrosis in we established a well in system of neonatal and that were or in system the cellular and in for expression of cytokines, and matrix We that the cardiomyocyte-cardiofibroblast is for a fibrogenic response and that Timp3−/− co-cultures have the to a fibrogenic response with co-cultures in response to neonatal co-cultures, the of for collagen M. S. E. S. Hypertension. PubMed Scopus Google Scholar). we show that co-cultures are at and The mechanism underlying the with TIMP3 increased as well as proteolytic processing of TGFβ1 and and of specific metalloproteinases of the in expression of collagen and cytokines, indicating toward matrix remodeling loss of a neonatal system we the role of in the fibrosis in Timp3−/− in vivo. The of TNF through the of mice or TGFβ1 by antibody to the of each TGFβ1 was induced in Timp3−/−/Tnf−/− antibody TNF indicating that the TGFβ1 may of Although TNF at in the with the at and that the in TNF the of in Timp3−/− heart is the key in the and and show that of the cardiac resulting from the loss of TIMP3 is due to its cytokines, anti-inflammatory and the It their of the of and resulting in tissue remodeling that leads to fibrosis.TGFβ1 is a key regulator of inflammation and fibrosis and is regulated at TGFβ1 mice a inflammatory and I. S. M. R. C. G. D. PubMed Scopus Google Scholar, D. A. M. S. Sci. PubMed Scopus Google Scholar), TGFβ1 in and fibrosis M. P. N. Lab. Invest. Google Scholar, N. P. J. P. L. Sci. PubMed Scopus Google Scholar). are increased in with fibrosis, and fibrosis N. Engl. J. Med. 2000; PubMed Scopus Google Scholar). of TGFβ1 are as in have with M. J. PubMed Google Scholar). TGFβ1 its of expression and can play a role in to N. Engl. J. Med. 2000; PubMed Scopus Google Scholar, A. M. P. Hypertension. PubMed Google Scholar). a that TGFβ1 been linked to the of M.R. A. P. P.J. PubMed Scopus Google Scholar), and that with of TGFβ1 is with P.J. W. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. J. Y. H. M. M. H. A. K. J. Res. PubMed Scopus Google Scholar). The of for the ECM-bound is by the proteolytic release by with the loss of TIMP3 resulting in fibrosis, diastolic and of the by an antibody (1D11) fibrosis. of diastolic the in the diastolic were in mice a following The in diastolic in mice be due to function. are with a role of cytokine signaling in and diastolic fibrosis and diastolic heart failure L. C. Cardiovasc. Res. 2000; PubMed Scopus Google Scholar, M. J. PubMed Scopus Google Scholar, K. K. J. J. 2004; PubMed Scopus Google Scholar). is a of and A reported the of fibrosis in of heart was observed A. P.J. PubMed Scopus Google Scholar). TIMP3 are in with and heart failure A.M. Y. C.F. Circulation. PubMed Scopus Google Scholar), and as we the loss of a TIMP3 in mice leads to fibrosis. Thus, TIMP3 can be a in strategies at fibrosis at early of heart Tissue repair requires the coordinated response between cellular and stromal compartments, involving regulated cytokine release, inflammation, cellular turnover, and structural remodeling, in order to restore organ function. The consequence of an inadequate remodeling program is reflected as necrosis, hyperplasia, and fibrosis, which are the hallmarks of multiple human diseases. Tissue fibrosis is the outcome of excessive and disorganized deposition of extracellular matrix (ECM) 3The abbreviations used are: ECMextracellular matrixAng IIangiotensin IIPEphenylephrineTGFβtransforming growth factor βTNFtumor necrosis factorMMPmatrix metalloproteinaseABaortic bandingWTwild typePSRPicro-Sirius RedELISAenzyme-linked immunosorbent assayCTcycle thresholdqPCRquantitative PCR. 3The abbreviations used are: ECMextracellular matrixAng IIangiotensin IIPEphenylephrineTGFβtransforming growth factor βTNFtumor necrosis factorMMPmatrix metalloproteinaseABaortic bandingWTwild typePSRPicro-Sirius RedELISAenzyme-linked immunosorbent assayCTcycle thresholdqPCRquantitative PCR. proteins, resulting in disruption of normal tissue architecture and homeostasis that contributes to organ dysfunction. Myocardial fibrosis is the underlying cause of diastolic heart failure and a complicating factor in multiple heart disorders (1Zile M.R. Baicu C.F. Gaasch W.H. N. Engl. J. Med. 2004; 350: 1953-1959Crossref PubMed Scopus (1179) Google Scholar, 2Katz A.M. Zile M.R. Circulation. 2006; 113: 1922-1925Crossref PubMed Scopus (81) Google Scholar, 3Herpel E. Pritsch M. Koch A. Dengler T.J. Schirmacher P. Schnabel P.A. Histopathology. 2006; 48: 736-747Crossref PubMed Scopus (56) Google Scholar). Although cell surface-bound and soluble matrix metalloproteinases (MMPs) along with their natural tissue inhibitors (tissue inhibitors of metalloproteinase) constitute an important system for regulating ECM turnover (4Spinale F.G. Physiol. Rev. 2007; 87: 1285-1342Crossref PubMed Scopus (892) Google Scholar), inflammation is emerging as an important co-contributor to fibrosis (5Stramer B.M. Mori R. Martin P. J. Invest. Dermatol. 2007; 127: 1009-1017Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 6Sugimoto H. Grahovac G. Zeisberg M. Kalluri R. Diabetes. 2007; 56: 1825-1833Crossref PubMed Scopus (183) Google Scholar). Recent studies have linked specific subsets of metalloproteinases to inflammatory processes through their ability to cleave a wide variety of ECM-bound and cell surface cytokines (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 8Murphy G. Murthy A. Khokha R. Trends Immunol. 2008; 29: 75-82Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Common regulators of inflammatory cytokines and fibrogenic ligands may be the key to building an adequate tissue response, and their identification can lead to developing new strategies against tissue fibrosis. extracellular matrix transforming growth factor tumor necrosis factor matrix metalloproteinase immunosorbent PCR. extracellular matrix transforming growth factor tumor necrosis factor matrix metalloproteinase immunosorbent PCR. TGFβ1 is considered the major regulator of fibroblast response during normal ECM homeostasis as well as during the pathogenesis of fibrosis (9Gauldie J. Bonniaud P. Sime P. Ask K. Kolb M. Biochem. Soc. Trans. 2007; 35: 661-664Crossref PubMed Scopus (153) Google Scholar). TGFβ1-activated fibroblasts, characterized by the expression of α-smooth muscle actin, are the main source of collagen biosynthesis in the myocardium (10Stawowy P. Kallisch H. Veinot J.P. Kilimnik A. Prichett W. Goetze S. Seidah N.G. Chrétien M. Fleck E. Graf K. Circulation. 2004; 109: 770-776Crossref PubMed Scopus (32) Google Scholar). TGFβ1 can trigger the differentiation of cardiac fibroblasts to activated myofibroblasts that synthesize collagen types I and III (11Petrov V.V. Fagard R.H. Lijnen P.J. Hypertension. 2002; 39: 258-263Crossref PubMed Scopus (339) Google Scholar, 12Asano Y. Ihn H. Yamane K. Kubo M. Tamaki K. J. Clin. Invest. 2004; 113: 253-264Crossref PubMed Scopus (196) Google Scholar). It also regulates the proteolytic systems responsible for ECM turnover (13Overall C.M. Wrana J.L. Sodek J. J. Biol. Chem. 1991; 266: 14064-14071Abstract Full Text PDF PubMed Google Scholar). Secreted TGFβ1 is sequestered and concentrated in the ECM by specific binding proteins, which render it biologically inactive (14Hyytiäinen M. Penttinen C. Keski-Oja J. Crit. Rev. Clin. Lab. Sci. 2004; 41: 233-264Crossref PubMed Scopus (272) Google Scholar). Enhanced TGFβ1 signaling can result from defective matrix-binding due to fibrillin mutations as observed in Marfan syndrome or by increased release from the ECM through excessive proteolysis (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 15Mu D. Cambier S. Fjellbirkeland L. Baron J.L. Munger J.S. Kawakatsu H. Sheppard D. Broaddus V.C. Nishimura S.L. J. Cell Biol. 2002; 157: 493-507Crossref PubMed Scopus (584) Google Scholar, 16Jenkins G. Int. J. Biochem. Cell Biol. 2008; 40: 1068-1078Crossref PubMed Scopus (242) Google Scholar). As such, MMP2, -9, and -14 have been suggested to activate latent TGFβ1 directly, via cleavage and release of latency-associated peptide (7Yu Q. Stamenkovic I. Genes Dev. 2000; 14: 163-176PubMed Google Scholar, 15Mu D. Cambier S. Fjellbirkeland L. Baron J.L. Munger J.S. Kawakatsu H. Sheppard D. Broaddus V.C. Nishimura S.L. J. Cell Biol. 2002; 157: 493-507Crossref PubMed Scopus (584) Google Scholar). MMPs and TGFβ1 also play a role in fibroblast migration (17Stawowy P. Margeta C. Kallisch H. Seidah N.G. Chrétien M. Fleck E. Graf K. Cardiovasc. Res. 2004; 63: 87-97Crossref PubMed Scopus (97) Google Scholar). Altogether, and TGFβ1 may at to tissue fibrosis. TGFβ1 and TNF are cytokines, and each the activated by the cytokine Y. S. S. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. D. A. M. Genes Dev. 2000; 14: Google Scholar). fibrosis, for a that can or collagen to the response J. J. Physiol. 2007; PubMed Scopus Google Scholar). TNF been to TGFβ1 signaling through its which the 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, C. J. Invest. Dermatol. 2007; 127: Full Text Full Text PDF PubMed Scopus Google Scholar), of cross-talk between TGFβ1 and TNF as to ECM and cell G. Murthy A. Khokha R. Trends Immunol. 2008; 29: 75-82Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, M. Penttinen C. Keski-Oja J. Crit. Rev. Clin. Lab. Sci. 2004; 41: 233-264Crossref PubMed Scopus (272) Google Scholar). of the proteolytic cleavage of TNF the cell surface and of TGFβ1 to the to soluble an adequate of is critical for a coordinated cellular stress response, which in their extracellular Timp3−/− mice have an abnormal inflammatory response due to excessive TNF signaling J.L. Khokha R. 2004; PubMed Scopus Google Scholar, Khokha R. J. Immunol. 2006; PubMed Scopus Google Scholar). Timp3−/− are to mechanical stress induced by of the and with an early onset of heart due to increased and metalloproteinase TNF processing and ECM Khokha R. Res. PubMed Scopus Google Scholar). Here we show that Timp3−/− as well as mice fibrosis a to the role of cytokine signaling in fibrosis. a neonatal cardiomyocyte-cardiofibroblast and genetic and pharmacological in we the of and the ability of TIMP3 to cytokines in the is a well established to cardiac the in with or tissue a coordinated response between cellular and stromal through the of cytokines that are regulated in and We show that TIMP3 is a common stromal regulator of critical proinflammatory (TNF) and anti-inflammatory cytokines in and its loss a distinct gene expression program The of cytokines at the of expression and maturation involving proteolytic to their as through the activation of their in TIMP3 reciprocal an cross-talk responsible for the tissue remodeling, which in fibrosis, and heart to in gene expression suggested an early of TGFβ1 in Timp3−/− mice the that TGFβ1 is responsible for fibrosis in we established a well in system of neonatal and that were or in system the cellular and in for expression of cytokines, and matrix We that the cardiomyocyte-cardiofibroblast is for a fibrogenic response and that Timp3−/− co-cultures have the to a fibrogenic response with co-cultures in response to neonatal co-cultures, the of for collagen M. S. E. S. Hypertension. PubMed Scopus Google Scholar). we show that co-cultures are at and The mechanism underlying the with TIMP3 increased as well as proteolytic processing of TGFβ1 and and of specific metalloproteinases of the in expression of collagen and cytokines, indicating toward matrix remodeling loss of a neonatal system we the role of in the fibrosis in Timp3−/− in vivo. The of TNF through the of mice or TGFβ1 by antibody to the of each TGFβ1 was induced in Timp3−/−/Tnf−/− antibody TNF indicating that the TGFβ1 may of Although TNF at in the with the at and that the in TNF the of in Timp3−/− heart is the key in the and and show that of the cardiac resulting from the loss of TIMP3 is due to its cytokines, anti-inflammatory and the It their of the of and resulting in tissue remodeling that leads to fibrosis.TGFβ1 is a key regulator of inflammation and fibrosis and is regulated at TGFβ1 mice a inflammatory and I. S. M. R. C. G. D. PubMed Scopus Google Scholar, D. A. M. S. Sci. PubMed Scopus Google Scholar), TGFβ1 in and fibrosis M. P. N. Lab. Invest. Google Scholar, N. P. J. P. L. Sci. PubMed Scopus Google Scholar). are increased in with fibrosis, and fibrosis N. Engl. J. Med. 2000; PubMed Scopus Google Scholar). of TGFβ1 are as in have with M. J. PubMed Google Scholar). TGFβ1 its of expression and can play a role in to N. Engl. J. Med. 2000; PubMed Scopus Google Scholar, A. M. P. Hypertension. PubMed Google Scholar). a that TGFβ1 been linked to the of M.R. A. P. P.J. PubMed Scopus Google Scholar), and that with of TGFβ1 is with P.J. W. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. J. Y. H. M. M. H. A. K. J. Res. PubMed Scopus Google Scholar). The of for the ECM-bound is by the proteolytic release by with the loss of TIMP3 resulting in fibrosis, diastolic and of the by an antibody (1D11) fibrosis. of diastolic the in the diastolic were in mice a following The in diastolic in mice be due to function. are with a role of cytokine signaling in and diastolic fibrosis and diastolic heart failure L. C. Cardiovasc. Res. 2000; PubMed Scopus Google Scholar, M. J. PubMed Scopus Google Scholar, K. K. J. J. 2004; PubMed Scopus Google Scholar). is a of and A reported the of fibrosis in of heart was observed A. P.J. PubMed Scopus Google Scholar). TIMP3 are in with and heart failure A.M. Y. C.F. Circulation. PubMed Scopus Google Scholar), and as we the loss of a TIMP3 in mice leads to fibrosis. Thus, TIMP3 can be a in strategies at fibrosis at early of heart is a well established to cardiac the in with or tissue a coordinated response between cellular and stromal through the of cytokines that are regulated in and We show that TIMP3 is a common stromal regulator of critical proinflammatory (TNF) and anti-inflammatory cytokines in and its loss a distinct gene expression program The of cytokines at the of expression and maturation involving proteolytic to their as through the activation of their in TIMP3 reciprocal an cross-talk responsible for the tissue remodeling, which in fibrosis, and heart failure. Microarray to in gene expression suggested an early of TGFβ1 in Timp3−/− mice the that TGFβ1 is responsible for fibrosis in we established a well in system of neonatal and that were or in system the cellular and in for expression of cytokines, and matrix We that the cardiomyocyte-cardiofibroblast is for a fibrogenic response and that Timp3−/− co-cultures have the to a fibrogenic response with co-cultures in response to neonatal co-cultures, the of for collagen M. S. E. S. Hypertension. PubMed Scopus Google Scholar). we show that co-cultures are at and The mechanism underlying the with TIMP3 increased as well as proteolytic processing of TGFβ1 and and of specific metalloproteinases of the in expression of collagen and cytokines, indicating toward matrix remodeling loss of a neonatal system we the role of in the fibrosis in Timp3−/− in vivo. The of TNF through the of mice or TGFβ1 by antibody to the of each TGFβ1 was induced in Timp3−/−/Tnf−/− antibody TNF indicating that the TGFβ1 may of Although TNF at in the with the at and that the in TNF the of in Timp3−/− heart is the key in the and and show that of the cardiac resulting from the loss of TIMP3 is due to its cytokines, anti-inflammatory and the It their of the of and resulting in tissue remodeling that leads to fibrosis. TGFβ1 is a key regulator of inflammation and fibrosis and is regulated at TGFβ1 mice a inflammatory and I. S. M. R. C. G. D. PubMed Scopus Google Scholar, D. A. M. S. Sci. PubMed Scopus Google Scholar), TGFβ1 in and fibrosis M. P. N. Lab. Invest. Google Scholar, N. P. J. P. L. Sci. PubMed Scopus Google Scholar). are increased in with fibrosis, and fibrosis N. Engl. J. Med. 2000; PubMed Scopus Google Scholar). of TGFβ1 are as in have with M. J. PubMed Google Scholar). TGFβ1 its of expression and can play a role in to N. Engl. J. Med. 2000; PubMed Scopus Google Scholar, A. M. P. Hypertension. PubMed Google Scholar). a that TGFβ1 been linked to the of M.R. A. P. P.J. PubMed Scopus Google Scholar), and that with of TGFβ1 is with P.J. W. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. A. J. Y. H. M. M. H. A. K. J. Res. PubMed Scopus Google Scholar). The of for the ECM-bound is by the proteolytic release by with the loss of TIMP3 resulting in fibrosis, diastolic and of the by an antibody (1D11) fibrosis. of diastolic the in the diastolic were in mice a following The in diastolic in mice be due to function. are with a role of cytokine signaling in and diastolic Myocardial fibrosis and diastolic heart failure L. C. Cardiovasc. Res. 2000; PubMed Scopus Google Scholar, M. J. PubMed Scopus Google Scholar, K. K. J. J. 2004; PubMed Scopus Google Scholar). is a of and A reported the of fibrosis in of heart was observed A. P.J. PubMed Scopus Google Scholar). TIMP3 are in with and heart failure A.M. Y. C.F. Circulation. PubMed Scopus Google Scholar), and as we the loss of a TIMP3 in mice leads to fibrosis. Thus, TIMP3 can be a in strategies at fibrosis at early of heart We Murthy and for critical of the with with

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