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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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Related in: MedlinePlus

Effects of MURF1 on cardiac cell size and sarcomere organization. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE or PMA for 48 h. The cells were observed under a fluorescent microscope with a 20× objective lens. (B) Approximately 150–200 cells per condition were measured for cell surface area using the ImageJ program. The data are presented as means ± SEM. *, P < 0.05 compared with control. (C) After induction with PE or PMA, cells were fixed and immunostained with mouse anti-α-actinin antibody (blue). (D) Insets reveal sarcomeric organization in myocytes.
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fig9: Effects of MURF1 on cardiac cell size and sarcomere organization. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE or PMA for 48 h. The cells were observed under a fluorescent microscope with a 20× objective lens. (B) Approximately 150–200 cells per condition were measured for cell surface area using the ImageJ program. The data are presented as means ± SEM. *, P < 0.05 compared with control. (C) After induction with PE or PMA, cells were fixed and immunostained with mouse anti-α-actinin antibody (blue). (D) Insets reveal sarcomeric organization in myocytes.

Mentions: To further characterize the effects of MURF1 on cardiomyocyte hypertrophy, we examined how the activity of MURF1 modulated cell size and sarcomeric organization in NRVM. As expected, PE treatment of GFP-infected cardiomyocytes led to increased cell size compared with untreated cells (Fig. 9 A). In the presence of Ad.MURF1, the response to PE was dramatically reduced. To quantitate the extent of hypertrophy, a total of 150–200 cells in each treatment were scored for their cell surface areas. Treatment of cardiomyocytes with PE for 48 h resulted in a threefold increase in cell size. MURF1 completely abolished the PE- and PMA-induced increase in myocyte size, but not the changes induced by IGF-I (Fig. 9 B). The specificity of MURF1 effects on hypertrophy was further substantiated by studying the effect of a similar ring finger ubiquitin ligase protein, CHIP. CHIP had no effect on agonist-induced increases in cell size (Fig. 9 B).


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)

Effects of MURF1 on cardiac cell size and sarcomere organization. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE or PMA for 48 h. The cells were observed under a fluorescent microscope with a 20× objective lens. (B) Approximately 150–200 cells per condition were measured for cell surface area using the ImageJ program. The data are presented as means ± SEM. *, P < 0.05 compared with control. (C) After induction with PE or PMA, cells were fixed and immunostained with mouse anti-α-actinin antibody (blue). (D) Insets reveal sarcomeric organization in myocytes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172633&req=5

fig9: Effects of MURF1 on cardiac cell size and sarcomere organization. (A) NRVM were infected with Ad.GFP or Ad.MURF1 for 24 h followed by induction with PE or PMA for 48 h. The cells were observed under a fluorescent microscope with a 20× objective lens. (B) Approximately 150–200 cells per condition were measured for cell surface area using the ImageJ program. The data are presented as means ± SEM. *, P < 0.05 compared with control. (C) After induction with PE or PMA, cells were fixed and immunostained with mouse anti-α-actinin antibody (blue). (D) Insets reveal sarcomeric organization in myocytes.
Mentions: To further characterize the effects of MURF1 on cardiomyocyte hypertrophy, we examined how the activity of MURF1 modulated cell size and sarcomeric organization in NRVM. As expected, PE treatment of GFP-infected cardiomyocytes led to increased cell size compared with untreated cells (Fig. 9 A). In the presence of Ad.MURF1, the response to PE was dramatically reduced. To quantitate the extent of hypertrophy, a total of 150–200 cells in each treatment were scored for their cell surface areas. Treatment of cardiomyocytes with PE for 48 h resulted in a threefold increase in cell size. MURF1 completely abolished the PE- and PMA-induced increase in myocyte size, but not the changes induced by IGF-I (Fig. 9 B). The specificity of MURF1 effects on hypertrophy was further substantiated by studying the effect of a similar ring finger ubiquitin ligase protein, CHIP. CHIP had no effect on agonist-induced increases in cell size (Fig. 9 B).

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