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Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy.

Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C - J. Cell Biol. (2004)

Bottom Line: Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy.MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1.MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size.

View Article: PubMed Central - PubMed

Affiliation: Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy. In spite of this, we still know little about the mechanisms that inhibit hypertrophic growth. We define a novel anti-hypertrophic signaling pathway regulated by muscle ring finger protein-1 (MURF1) that inhibits the agonist-stimulated PKC-mediated signaling response in neonatal rat ventricular myocytes. MURF1 interacts with receptor for activated protein kinase C (RACK1) and colocalizes with RACK1 after activation with phenylephrine or PMA. Coincident with this agonist-stimulated interaction, MURF1 blocks PKCepsilon translocation to focal adhesions, which is a critical event in the hypertrophic signaling cascade. MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1. MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size. These findings establish that MURF1 is a key regulator of the PKC-dependent hypertrophic response and can blunt cardiomyocyte hypertrophy, which may have important implications in the pathophysiology of clinical cardiac hypertrophy.

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MURF1 inhibits adrenergic agonist-induced cardiac gene expression. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE for 48 h. The cells were followed by immunostaining with rabbit anti-ANF antibody (red). (B) After adenoviral infection for 24 h in serum-free medium, cells were induced with PE, Ang II, IGF-1, endothelin-1 (ET-1), and serum for 24 h. mRNA was isolated and subjected to RT-PCR using primers specific to skeletal α-actin, ANF, β-MHC, and GAPDH.
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fig8: MURF1 inhibits adrenergic agonist-induced cardiac gene expression. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE for 48 h. The cells were followed by immunostaining with rabbit anti-ANF antibody (red). (B) After adenoviral infection for 24 h in serum-free medium, cells were induced with PE, Ang II, IGF-1, endothelin-1 (ET-1), and serum for 24 h. mRNA was isolated and subjected to RT-PCR using primers specific to skeletal α-actin, ANF, β-MHC, and GAPDH.

Mentions: Activation of both PKC and FAK leads to cellular changes indicative of hypertrophy, including increased cell size, sarcomeric organization, and induction of hypertrophic markers such as atrial natriuretic factor (ANF). To test the hypothesis that MURF1 antagonizes initiation of the hypertrophic response, we infected NRVM with Ad.GFP or Ad.MURF1, followed by stimulation with PE for 48 h. Immunohistochemical analysis indicated that ANF was induced after PE treatment in the perinuclear region in the Ad.GFP-infected NRVM as expected, but this effect was inhibited in Ad.MURF1-infected cells (Fig. 8 A). Similar results were observed after treatment with PMA (unpublished data). Next, we examined the expression of ANF, α-actin, and β-myosin heavy chain mRNA in cardiomyocytes treated with PE, angiotensin-II, endothelin-1, insulin-like growth factor 1 (IGF-1), or serum, in the presence and absence of Ad.MURF1 by RT-PCR. The basal level of these mRNAs was detected in myocytes as reported previously (Sekiguchi et al., 1999). Exposure to each of these agonists resulted in up-regulation of these hypertrophic markers, and in each case (except for IGF-1) up-regulation was blocked by increased expression of MURF1 (Fig. 8 B). These data indicate that MURF1 inhibits G protein–coupled receptor-dependent expression of hypertrophic markers in cardiomyocytes.


Muscle ring finger protein-1 inhibits PKC{epsilon} activation and prevents cardiomyocyte hypertrophy.

Arya R, Kedar V, Hwang JR, McDonough H, Li HH, Taylor J, Patterson C - J. Cell Biol. (2004)

MURF1 inhibits adrenergic agonist-induced cardiac gene expression. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE for 48 h. The cells were followed by immunostaining with rabbit anti-ANF antibody (red). (B) After adenoviral infection for 24 h in serum-free medium, cells were induced with PE, Ang II, IGF-1, endothelin-1 (ET-1), and serum for 24 h. mRNA was isolated and subjected to RT-PCR using primers specific to skeletal α-actin, ANF, β-MHC, and GAPDH.
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Related In: Results  -  Collection

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fig8: MURF1 inhibits adrenergic agonist-induced cardiac gene expression. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE for 48 h. The cells were followed by immunostaining with rabbit anti-ANF antibody (red). (B) After adenoviral infection for 24 h in serum-free medium, cells were induced with PE, Ang II, IGF-1, endothelin-1 (ET-1), and serum for 24 h. mRNA was isolated and subjected to RT-PCR using primers specific to skeletal α-actin, ANF, β-MHC, and GAPDH.
Mentions: Activation of both PKC and FAK leads to cellular changes indicative of hypertrophy, including increased cell size, sarcomeric organization, and induction of hypertrophic markers such as atrial natriuretic factor (ANF). To test the hypothesis that MURF1 antagonizes initiation of the hypertrophic response, we infected NRVM with Ad.GFP or Ad.MURF1, followed by stimulation with PE for 48 h. Immunohistochemical analysis indicated that ANF was induced after PE treatment in the perinuclear region in the Ad.GFP-infected NRVM as expected, but this effect was inhibited in Ad.MURF1-infected cells (Fig. 8 A). Similar results were observed after treatment with PMA (unpublished data). Next, we examined the expression of ANF, α-actin, and β-myosin heavy chain mRNA in cardiomyocytes treated with PE, angiotensin-II, endothelin-1, insulin-like growth factor 1 (IGF-1), or serum, in the presence and absence of Ad.MURF1 by RT-PCR. The basal level of these mRNAs was detected in myocytes as reported previously (Sekiguchi et al., 1999). Exposure to each of these agonists resulted in up-regulation of these hypertrophic markers, and in each case (except for IGF-1) up-regulation was blocked by increased expression of MURF1 (Fig. 8 B). These data indicate that MURF1 inhibits G protein–coupled receptor-dependent expression of hypertrophic markers in cardiomyocytes.

Bottom Line: Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy.MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1.MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size.

View Article: PubMed Central - PubMed

Affiliation: Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Much effort has focused on characterizing the signal transduction cascades that are associated with cardiac hypertrophy. In spite of this, we still know little about the mechanisms that inhibit hypertrophic growth. We define a novel anti-hypertrophic signaling pathway regulated by muscle ring finger protein-1 (MURF1) that inhibits the agonist-stimulated PKC-mediated signaling response in neonatal rat ventricular myocytes. MURF1 interacts with receptor for activated protein kinase C (RACK1) and colocalizes with RACK1 after activation with phenylephrine or PMA. Coincident with this agonist-stimulated interaction, MURF1 blocks PKCepsilon translocation to focal adhesions, which is a critical event in the hypertrophic signaling cascade. MURF1 inhibits focal adhesion formation, and the activity of downstream effector ERK1/2 is also inhibited in the presence of MURF1. MURF1 inhibits phenylephrine-induced (but not IGF-1-induced) increases in cell size. These findings establish that MURF1 is a key regulator of the PKC-dependent hypertrophic response and can blunt cardiomyocyte hypertrophy, which may have important implications in the pathophysiology of clinical cardiac hypertrophy.

Show MeSH
Related in: MedlinePlus