Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

We previously demonstrated that aldosterone, which stimulates collagen production through the mineralocorticoid receptor (MR)-dependent pathway, also induces elastogenesis via a parallel MR-independent mechanism involving insulin-like growth factor-I receptor (IGF-IR) signaling. The present study provides a more detailed explanation of this signaling pathway. Our data demonstrate that small interfering RNA-driven elimination of MR in cardiac fibroblasts does not inhibit aldosterone-induced IGF-IR phosphorylation and subsequent increase in elastin production. These results exclude the involvement of the MR in aldosterone-induced increases in elastin production. Results of further experiments aimed at identifying the upstream signaling component(s) that might be activated by aldosterone also eliminate the putative involvement of pertussis toxin-sensitive Gαi proteins, which have previously been shown to be responsible for some MR-independent effects of aldosterone. Instead, we found that small interfering RNA-dependent elimination of another heterotrimeric G protein, Gα13, eliminates aldosterone-induced elastogenesis. We further demonstrate that aldosterone first engages Gα13 and then promotes its transient interaction with c-Src, which constitutes a prerequisite step for aldosterone-dependent activation of the IGF-IR and propagation of consecutive downstream elastogenic signaling involving phosphatidylinositol 3-kinase/Akt. In summary, the data we present reveal new details of an MR-independent cellular signaling pathway through which aldosterone stimulates elastogenesis in human cardiac fibroblasts. We previously demonstrated that aldosterone, which stimulates collagen production through the mineralocorticoid receptor (MR)-dependent pathway, also induces elastogenesis via a parallel MR-independent mechanism involving insulin-like growth factor-I receptor (IGF-IR) signaling. The present study provides a more detailed explanation of this signaling pathway. Our data demonstrate that small interfering RNA-driven elimination of MR in cardiac fibroblasts does not inhibit aldosterone-induced IGF-IR phosphorylation and subsequent increase in elastin production. These results exclude the involvement of the MR in aldosterone-induced increases in elastin production. Results of further experiments aimed at identifying the upstream signaling component(s) that might be activated by aldosterone also eliminate the putative involvement of pertussis toxin-sensitive Gαi proteins, which have previously been shown to be responsible for some MR-independent effects of aldosterone. Instead, we found that small interfering RNA-dependent elimination of another heterotrimeric G protein, Gα13, eliminates aldosterone-induced elastogenesis. We further demonstrate that aldosterone first engages Gα13 and then promotes its transient interaction with c-Src, which constitutes a prerequisite step for aldosterone-dependent activation of the IGF-IR and propagation of consecutive downstream elastogenic signaling involving phosphatidylinositol 3-kinase/Akt. In summary, the data we present reveal new details of an MR-independent cellular signaling pathway through which aldosterone stimulates elastogenesis in human cardiac fibroblasts. Aldosterone is a major component of the renin-angiotensin-aldosterone system, which plays an important role in the regulation of electrolyte and fluid balance (1Jennings D.L. Kalus J.S. O'Dell K.M. Pharmacotherapy. 2005; 25: 1126-1133Crossref PubMed Scopus (6) Google Scholar, 2Connell J.M. Davies E. J. Endocrinol. 2005; 186: 1-20Crossref PubMed Scopus (263) Google Scholar). The majority of aldosterone-induced effects occur after it binds to the intracellular MR. The activated aldosterone-MR complex translocates to the nucleus, where it modulates the transcription and translation of “aldosterone-induced” proteins involved in blood pressure homeostasis. Aldosterone has also been implicated in the stimulation of collagen synthesis and myocardial fibrosis through a process that is independent of its effect on blood pressure (3Weber K.T. Brilla C.G. Circulation. 1991; 83: 1849-1865Crossref PubMed Scopus (1892) Google Scholar, 4Brilla C.G. Matsubara L.S. Weber K.T. Am. J. Cardiol. 1993; 71: 12A-16AAbstract Full Text PDF PubMed Scopus (262) Google Scholar, 5Young M. Fullerton M. Dilley R. Funder J. J. Clin. Investig. 1994; 93: 2578-2583Crossref PubMed Scopus (429) Google Scholar). Two clinical studies, the Randomized Aldactone Evaluation Study (6Pitt B. Zannad F. Remme W.J. Cody R. Castaigne A. Perez A. Palensky J. Wittes J. N. Engl. J. Med. 1999; 341: 709-717Crossref PubMed Scopus (7555) Google Scholar) and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (7Pitt B. Remme W. Zannad F. Neaton J. Martinez F. Roniker B. Bittman R. Hurley S. Kleiman J. Gatlin M. N. Engl. J. Med. 2003; 348: 1309-1321Crossref PubMed Scopus (4086) Google Scholar), demonstrated that low doses of MR 2The abbreviations used are: MRmineralocorticoid receptorECMextracellular matrixIGF-Iinsulin-like growth factor-IIGF-IRIGF-I receptorBSAbovine serum albuminMAPKmitogen-activated protein kinaseERKextracellular signal-regulated kinaseGPCRG protein-coupled receptorJNKc-Jun N-terminal kinaseRbretinoblastoma proteinsiRNAsmall interfering RNAPIphosphatidylinositol 3-kinaseGAPDHglyceraldehyde-3-phosphate dehydrogenaseRTreverse transcriptionMEKMAPK/ERK kinase.2The abbreviations used are: MRmineralocorticoid receptorECMextracellular matrixIGF-Iinsulin-like growth factor-IIGF-IRIGF-I receptorBSAbovine serum albuminMAPKmitogen-activated protein kinaseERKextracellular signal-regulated kinaseGPCRG protein-coupled receptorJNKc-Jun N-terminal kinaseRbretinoblastoma proteinsiRNAsmall interfering RNAPIphosphatidylinositol 3-kinaseGAPDHglyceraldehyde-3-phosphate dehydrogenaseRTreverse transcriptionMEKMAPK/ERK kinase. antagonists lead to a dramatic reduction in the mortality rate of patients who suffered acute myocardial infarctions. Despite the suggestion that these MR antagonists may alleviate maladaptive remodeling of the extracellular matrix (ECM) of post-infarct hearts (8Zannad F. Alla F. Dousset B. Perez A. Pitt B. Circulation. 2000; 102: 2700-2706Crossref PubMed Scopus (853) Google Scholar, 9Zannad F. Dousset B. Alla F. Hypertension. 2001; 38: 1227-1232Crossref PubMed Scopus (128) Google Scholar), the molecular mechanisms by which they improve overall heart function in those patients have not been fully resolved. mineralocorticoid receptor extracellular matrix insulin-like growth factor-I IGF-I receptor bovine serum albumin mitogen-activated protein kinase extracellular signal-regulated kinase G protein-coupled receptor c-Jun N-terminal kinase retinoblastoma protein small interfering RNA phosphatidylinositol 3-kinase glyceraldehyde-3-phosphate dehydrogenase reverse transcription MAPK/ERK kinase. mineralocorticoid receptor extracellular matrix insulin-like growth factor-I IGF-I receptor bovine serum albumin mitogen-activated protein kinase extracellular signal-regulated kinase G protein-coupled receptor c-Jun N-terminal kinase retinoblastoma protein small interfering RNA phosphatidylinositol 3-kinase glyceraldehyde-3-phosphate dehydrogenase reverse transcription MAPK/ERK kinase. It has been also shown that aldosterone can induce numerous effects in a wide range of nonepithelial tissues, including heart, and that it may act through membrane receptors other than the traditional MR (alternative receptors) in epithelial and nonepithelial tissue in a nongenomic manner (10Christ M. Sippel K. Eisen C. Wehling M. Mol. Cell. Endocrinol. 1994; 99: R31-R34Crossref PubMed Scopus (74) Google Scholar, 11Haseroth K. Gerdes D. Berger S. Feuring M. Günther A. Herbst C. Christ M. Wehling M. Biochem. Biophys. Res. Commun. 1999; 266: 257-261Crossref PubMed Scopus (125) Google Scholar, 12Chai W. Garrelds I.M. de Vries R. Batenburg W.W. van Kats J.P. Danser A.H. Hypertension. 2005; 46: 701-706Crossref PubMed Scopus (75) Google Scholar, 13Gekle M. Silbernagl S. Wünsch S. J. Physiol. 1998; 511: 255-263Crossref PubMed Scopus (51) Google Scholar). Although the classical genomic model of aldosterone action has long been accepted, the rapid, nongenomic mechanism of aldosterone action is not yet fully elucidated (2Connell J.M. Davies E. J. Endocrinol. 2005; 186: 1-20Crossref PubMed Scopus (263) Google Scholar). However, it has been proposed that some of these nongenomic effects of aldosterone also require the presence of MR or a closely related protein (14Mihailidou A.S. Steroids. 2006; 71: 277-280Crossref PubMed Scopus (20) Google Scholar). In contrast, other studies have shown that the nongenomic aldosterone effects still occur in cell lines lacking the classical MR and in yeast devoid of MR or in normal cells treated with MR antagonists (2Connell J.M. Davies E. J. Endocrinol. 2005; 186: 1-20Crossref PubMed Scopus (263) Google Scholar, 11Haseroth K. Gerdes D. Berger S. Feuring M. Günther A. Herbst C. Christ M. Wehling M. Biochem. Biophys. Res. Commun. 1999; 266: 257-261Crossref PubMed Scopus (125) Google Scholar, 15Böhmer S. Carapito C. Wilzewski B. Leize E. Van Dorsselaer A. Bernhardt R. Biol. Chem. 2006; 387: 917-929Crossref PubMed Scopus (9) Google Scholar). Such results strongly suggest the involvement of other receptor(s), distinct from the classic MR, that may interact with aldosterone and trigger the nongenomic effects of this hormone. Although full structural characterization of this putative receptor (or receptors) has not been completed yet (16Eisen C. Meyer C. Christ M. Theisen K. Wehling M. Cell. Mol. Biol. 1994; Google Scholar), data suggest that some MR-independent effects of aldosterone occur after activation of the pertussis toxin-sensitive heterotrimeric G proteins M. Silbernagl S. Wünsch S. J. Physiol. 1998; 511: 255-263Crossref PubMed Scopus (51) Google Scholar, J. Physiol. 2001; PubMed Scopus Google Scholar). Results of studies have a mechanism in which aldosterone and its antagonists the production of an important component that provides to tissues, including of the We that aldosterone can elastogenesis in of human cardiac fibroblasts via an MR-independent mechanism involving IGF-IR activation S. K. A. Am. J. Full Text Full Text PDF PubMed Scopus Google Scholar). We have another of in which aldosterone in with MR antagonists may the remodeling of the In the present study we that cardiac in which the production of MR has been by still the aldosterone-induced increase in elastin production. We also present the first that this MR-independent elastogenic effect of aldosterone can be by a signaling pathway that activation of the heterotrimeric G protein Gα13 and consecutive activation of c-Src, and signaling. aldosterone, protein pertussis human and and from and from from from bovine with and other cell from to from to collagen from c-Src, and and from and MR, and Gα13, normal or and and human cell from MR from and to an and the from from tissue for for and a from Two Gα13 from and a Gα13 MR from including and from aldosterone from by the aldosterone to through a on the of the a F. S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). We used cardiac fibroblasts from human hearts responsible for the production of cardiac to studies cardiac fibroblasts of a from in with an C. M. D. A. J. C. J. A.S. J. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). by and in with and bovine cells used in The of these at fibroblasts by for and for and cell previously Mol. 2000; PubMed Scopus Google Scholar). In experiments aimed at fibroblasts and in a normal the at which they then treated for with or of aldosterone Weber K.T. Mol. Cell. Biochem. PubMed Scopus Google Scholar). In experiments we also the of an of aldosterone that to which it from the cell demonstrated in studies C. A. C. F. M. F. N. M. J. Am. Google Scholar, S. Steroids. 2006; 71: PubMed Scopus Google Scholar). The G protein pertussis M. Silbernagl S. Wünsch S. J. Physiol. 1998; 511: 255-263Crossref PubMed Scopus (51) Google Scholar), kinase A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. S. A. M. M. A. Hypertension. 2005; 46: PubMed Scopus Google Scholar), W. A. S. S. A. 2001; PubMed Scopus Google Scholar, M. N. R. M. S. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), 3-kinase N. S. N. K. PubMed Scopus Google Scholar, S. K. N. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), kinase R. S. E. A. A. 2003; PubMed Scopus Google Scholar), and kinase M. K. J. M. S. PubMed Scopus Google Scholar, K. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the receptor M. K. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, S. J. K. A.H. J.M. Circulation. 1998; PubMed Scopus Google Scholar) and the receptor Am. J. Physiol. Heart Physiol. 1993; PubMed Google Scholar, J. Cardiol. PubMed Scopus Google Scholar), to aldosterone to aldosterone by the The cells also treated for with and previously M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). of the cell an of the the of the with the in at elastin and MR or in at collagen for and with normal serum for at The then for with of to of to MR, or of to collagen of the then for an with or to MR, and collagen The with used a of the then in and with a to a and a for human cardiac fibroblasts to in in of of to and treated in the a the cells with and the cells including and in of for to matrix elastin A. M. J. Biol. 1994; PubMed Scopus Google Scholar). The the elastin then by in of for and the in fluid and A. M. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). The from also used for to and J. 1998; PubMed Google Scholar) the from results the of elastin in the to and of human cardiac treated with or the in the for RNA the to the of RNA to and the to the in a of The reverse transcription step for elastin and at for by at The elastin to a the of for for and for and of for The Gα13 to a the of for for and for and of for The collagen the of for for and for and of for The to a the of for for and for and of for of the Gα13, collagen and from on a and with The of Gα13, and collagen to the of human cardiac with or the in the for the the of the cells an a of and of protein in and and the for The protein by to for an and then with or with at of the then with the for an and the in the the and experiments human cell also and with the that a and the molecular not The of or phosphorylation of signaling by the of human cardiac for the in the presence or of aldosterone or for with of in the with the in the the of the cells and of protein then for with normal at and with c-Src, or with Gα13 for at by the of protein and previously A. M. F. J. J. Clin. Investig. 1993; PubMed Scopus Google Scholar). The at and with The in and the proteins of the membrane and of c-Src, the those with with in the the and for of the also and used a and not a not The of or phosphorylation of signaling by MR a of MR from Two human Gα13 and from The to to on the human Gα13 The which previously shown to eliminate Gα13 in cells J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). and used for the fibroblasts in in with bovine and cardiac in and of Gα13, or or of MR or cells to the MR production by Gα13 by and in the The Gα13 the of Gα13 and used in experiments to Gα13 In of the studies, in in The and for and by of of than In study we demonstrated that with of aldosterone increases elastin and in a MR receptor aldosterone-induced increases in elastin which after aldosterone-dependent phosphorylation of IGF-IR S. K. A. Am. J. Full Text Full Text PDF PubMed Scopus Google Scholar). The present study to a detailed characterization of the signaling pathway through which aldosterone elastin production. We first used to eliminate the production of MR in cardiac to exclude the involvement of MR in aldosterone-induced elastogenesis. We first demonstrated that MR protein to of the after and to of after results of the consecutive experiments demonstrated that this of MR synthesis in of cardiac fibroblasts and not elastogenic to of aldosterone and we also that a to of aldosterone, which a transient increase in phosphorylation of the IGF-IR in a increase in treated with MR we aldosterone to this of aldosterone trigger IGF-IR phosphorylation by stimulation of a cell component (or for with of aldosterone the effect on IGF-IR phosphorylation with aldosterone The results that MR-independent activation of the IGF-IR to elastin production by aldosterone does not require the of this the cell We that an effect might be through the interaction of aldosterone with cell experiments aimed at identifying the of aldosterone-induced signaling to elastogenesis. by that some MR-independent effects of aldosterone may be through the of signaling W. Garrelds I.M. de Vries R. Batenburg W.W. van Kats J.P. Danser A.H. Hypertension. 2005; 46: 701-706Crossref PubMed Scopus (75) Google Scholar, A. E. C. R. C. B. Circulation. PubMed Scopus Google Scholar, F. S. Hypertension. PubMed Scopus Google Scholar), we first the that aldosterone-induced elastogenesis might the of Our results demonstrated that the of and receptor antagonists to of cardiac fibroblasts not elastogenic to aldosterone not the that receptors involved other also that MR-independent effects of aldosterone can be by activation of the pertussis toxin-sensitive heterotrimeric G protein Gαi M. Silbernagl S. Wünsch S. J. Physiol. 1998; 511: 255-263Crossref PubMed Scopus (51) Google Scholar, J. Physiol. 2001; PubMed Scopus Google Scholar), we then its involvement in aldosterone-induced elastogenesis. However, the data we demonstrated that of cardiac fibroblasts with pertussis does not the effect of aldosterone the putative involvement of Gαi proteins in this process also We on another of the G protein Gα13, which has been shown to nongenomic of C. A. C. S. A. F. Mol. Endocrinol. 2006; PubMed Scopus Google Scholar). Gα13 be involved in the of the cellular signaling to an aldosterone-induced increase in elastin we Gα13 to of after and protein production to and of and after in cardiac the of its related Our results that the aldosterone-induced increase in elastin in with not occur in in which Gα13 of cardiac fibroblasts that with Gα13 not demonstrate increase in elastin in to aldosterone and parallel with or with demonstrated elastin and of and elastin in to IGF-I we found that in to with which demonstrated a increase in IGF-IR with not demonstrate in IGF-IR phosphorylation aldosterone We also demonstrated that Gα13 is not involved in the effect of aldosterone and These results demonstrated that Gα13 is in the of the aldosterone-induced increase in elastogenesis that to IGF-IR Results from further experiments that this effect may also the activation of kinase on the that of an increase in elastin and the in production in the downstream signaling by Gα13 M. N. R. M. S. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. 2006; PubMed Scopus Google Scholar), we the involvement of and its downstream in aldosterone-dependent elastogenesis. of cardiac with a cell or with a kinase not eliminate the aldosterone-induced increase in elastin and elastin production in cardiac we that the pathway is not involved in the elastogenic effect of aldosterone not Instead, we have that Gα13 with proteins aldosterone on results of experiments that Gα13 and can be from cellular that in the presence and of aldosterone for or these proteins after of aldosterone We then activation of Gα13 its transient with We found that a of proteins, W. 1998; PubMed Scopus Google Scholar, Biol. Med. 2003; PubMed Scopus Google Scholar), also the interaction and Gα13 we found that from cellular treated with interaction with Gα13 than phosphorylation of at in the activation of the kinase the of R. Biochem. Biophys. Res. Commun. 2005; PubMed Scopus Google Scholar), we then aldosterone increase phosphorylation at with a that of cells treated with aldosterone phosphorylation of on with the We also demonstrated that this effect we also found that the Gα13 not demonstrate increase in phosphorylation in to aldosterone in to which demonstrated a increase in phosphorylation after with aldosterone These results further the that in cardiac fibroblasts aldosterone engages Gα13 signaling that in with c-Src, its that the IGF-IR receptor the effect of aldosterone on elastin we to which downstream IGF-IR signaling pathway, the or the MAPK/ERK pathway D. D. PubMed Scopus Google Scholar), the elastogenic Results from studies and demonstrated that the activation of the pathway by its not eliminate the elastogenic effect of aldosterone to a further increase in the production of elastin and with an that another not the elastogenic effect of aldosterone and the other results from and studies demonstrated that the of the 3-kinase to treated with aldosterone or IGF-I the elastogenic effects of and These results that the 3-kinase pathway the elastogenic and that of the parallel pathway further the elastogenic the of aldosterone-induced signaling with the downstream elastogenic pathway signaling through the IGF-IR its we this downstream signaling still occur after of with and in lacking that the aldosterone-induced increase in the phosphorylation of is in treated with the and in with Gα13 and we that the of to increase after to aldosterone, a and the of the the the aldosterone signaling and increase in elastin the data reveal the details of an elastogenic signaling pathway that is by aldosterone and the consecutive activation of Gα13, c-Src, and IGF-IR and its downstream signaling. We previously that aldosterone stimulates elastogenesis via IGF-IR signaling in and and of human cardiac in the presence of the S. K. A. Am. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Results of the experiments in this demonstrate that aldosterone still induces elastogenesis in cardiac in which the synthesis of MR protein is by the of these data further that the elastogenic effect of aldosterone is via an MR-independent we have that aldosterone the of IGF-IR phosphorylation of aldosterone that the signaling pathway to the MR-independent elastogenic effect of aldosterone may be after the interaction of this with a on the cell of cardiac fibroblasts. is further by other studies that have demonstrated the of for aldosterone in human K. Google Scholar) human M. Eisen C. Christ M. Mol. Cell. Endocrinol. PubMed Scopus Google Scholar) and in (10Christ M. Sippel K. Eisen C. Wehling M. Mol. Cell. Endocrinol. 1994; 99: R31-R34Crossref PubMed Scopus (74) Google Scholar) and C. Christ M. Wehling M. J. Biochem. PubMed Scopus Google Scholar). It has also been that a protein may the for the cell receptor for aldosterone M. Eisen C. Christ M. Mol. Cell. Endocrinol. PubMed Scopus Google Scholar). However, this putative aldosterone receptor that MR-independent action has not been have that G protein-coupled receptors involved in the propagation of effects of other in Wehling M. PubMed Scopus Google Scholar, M. S. A. 2003; PubMed Scopus Google Scholar) and Mol. Endocrinol. 2000; PubMed Google Scholar, Mol. Endocrinol. PubMed Scopus Google Scholar, E. Steroids. PubMed Scopus Google Scholar, J. S. A. 2003; PubMed Scopus Google Scholar) and that some MR-independent effects of aldosterone can also be through pertussis toxin-sensitive Gαi proteins M. Silbernagl S. Wünsch S. J. Physiol. 1998; 511: 255-263Crossref PubMed Scopus (51) Google Scholar, J. Physiol. 2001; PubMed Scopus Google Scholar), we first Gαi the elastogenic effect of aldosterone. However, the results of in the that activation of Gαi may be involved in aldosterone-induced elastogenesis. Instead, we demonstrated for the first that another heterotrimeric protein, a of the Gα13, in a cellular to aldosterone that IGF-IR activation and a of elastogenesis. on data that the elimination of Gα13 in cardiac fibroblasts by the aldosterone-induced increase in IGF-IR phosphorylation and subsequent elastin production the we also demonstrated that the of the Gα13 protein not eliminate the elastogenic of IGF-I also that Gα13 is upstream of the IGF-IR in the elastogenic signaling pathway by aldosterone. Although studies have also shown that Gα13 can the activation of the kinase in cell including cardiac M. N. R. M. S. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. 2006; PubMed Scopus Google Scholar, R. J. Am. J. Physiol. Physiol. 2003; PubMed Scopus Google Scholar, M. F. K. M. Biochem. Biophys. Res. Commun. 2006; PubMed Scopus Google Scholar, S. M. C. A. M. C. Biochem. J. 2006; PubMed Scopus Google Scholar, K. F. J. 2001; PubMed Scopus Google Scholar, B. S. J. Biol. 1999; PubMed Scopus Google Scholar), the results of experiments demonstrated that with aldosterone the transient interaction Gα13 and the of its the elastogenic effect of aldosterone, we that the action of this kinase constitutes a prerequisite for the propagation of the aldosterone-dependent elastogenic It has been previously shown that Gα13 can and proteins 2003; PubMed Scopus Google Scholar), including S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (74) Google Scholar). we not the interaction Gα13 and is or it other proteins, that might and phosphorylation of S. J. PubMed Scopus Google Scholar, J. S. S. PubMed Google Scholar). We have that in cardiac Gα13 stimulates phosphorylation of c-Src, via the pathway and that the consecutive of elastogenic signaling phosphorylation of the IGF-IR and its downstream signaling pathway It has been previously shown that may not the IGF-IR on also increase the phosphorylation of this receptor on Weber J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which has been implicated a D. J. 1993; PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We may that aldosterone-induced activation IGF-IR signaling by its in promotes the downstream pathway for elastogenesis not the MAPK/ERK signaling pathway. Our to be by data that the aldosterone-induced elastogenic effect in the presence of the with an another not the elastogenic effect of aldosterone and phosphorylation on of the which is closely related to the has been shown to an role in signaling A. K. K. R. J. Biol. Chem. Full Text PDF PubMed Google Scholar), we also that the aldosterone-induced signaling phosphorylation of on the IGF-IR may to the mechanism the balance and studies to this In this study we not further the elastogenic mechanism in which IGF-I induces an increase in elastin It has been previously that in cells M. J. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (74) Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (75) Google Scholar) IGF-I induces an increase in elastin via a mechanism involving the of a retinoblastoma protein that for activation of the elastin by on its retinoblastoma J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (74) Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (75) Google Scholar). downstream of the of signaling pathway A. Biol. 2003; PubMed Scopus Google Scholar), we may that the aldosterone-dependent activation of this signaling pathway also modulates the interaction and transcription M. J. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (74) Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (75) Google Scholar), to an increase in elastin in cardiac fibroblasts. we found that of the MAPK/ERK signaling pathway further the effect of aldosterone on elastin production and we may also suggest that the signaling pathway induces elastogenesis by the phosphorylation of the MAPK/ERK pathway this a effect involving the signaling pathway has been in fibroblasts after to growth M. Am. J. Physiol. Mol. Physiol. PubMed Scopus Google Scholar). In summary, the data in this study suggest that the elastogenic effect of aldosterone in cardiac fibroblasts is through the MR-independent action of this hormone. mechanism a still (or that to Gα13 to c-Src, which in the activation of phosphorylation of the IGF-IR and its downstream 3-kinase signaling pathway signaling pathway to the of the elastin and the production of by cardiac fibroblasts. We that the production of that results from the MR-independent action of aldosterone may maladaptive fibrosis in the post-infarct heart in patients MR to the cardiac and normal

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