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The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression.

Kelloniemi A, Szabo Z, Serpi R, Näpänkangas J, Ohukainen P, Tenhunen O, Kaikkonen L, Koivisto E, Bagyura Z, Kerkelä R, Leosdottir M, Hedner T, Melander O, Ruskoaho H, Rysä J - PLoS ONE (2015)

Bottom Line: We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects.When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle.In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550).

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.

ABSTRACT
The phosphatase and actin regulator 1 (PHACTR1) locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal α-actin to cardiac α-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal α-actin to cardiac α-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550). Phactr1 seems to regulate the skeletal to cardiac α-actin isoform ratio.

No MeSH data available.


Related in: MedlinePlus

Phactr1 mRNA and protein levels are reduced 1 day after experimental myocardial infarction (MI) in rats.A) Phactr1 mRNA levels measured by RT-PCR and B) Phactr1 total protein levels analyzed by Western blot from the LV tissue samples 1 day, 2 weeks and 4 weeks after MI (n = 6–16). Open bars represent sham and solid bars MI **P<0.01, ***P<0.001 versus sham (Student’s t-test). C) Phactr1 and BNP mRNA levels in mechanically stretched neonatal ventricular myocytes in vitro. D) Phactr1 mRNA levels in response to p38 MAPK overexpression in neonatal ventricular myocytes in vitro (n = 5–9).*P<0.05, **P<0.01, ***P<0.001 versus control (Ctrl) or LacZ; ƗƗƗP<0.001 versus group at 4h (one-way ANOVA followed by least significance difference post hoc test). E) PHACTR1 total protein levels assessed by Western blot analyses from human heart samples (n = 2–4). **P<0.01 versus control hearts (Student’s t-test). The results are expressed as mean±SEM. Representative Western blots are shown.
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pone.0130502.g001: Phactr1 mRNA and protein levels are reduced 1 day after experimental myocardial infarction (MI) in rats.A) Phactr1 mRNA levels measured by RT-PCR and B) Phactr1 total protein levels analyzed by Western blot from the LV tissue samples 1 day, 2 weeks and 4 weeks after MI (n = 6–16). Open bars represent sham and solid bars MI **P<0.01, ***P<0.001 versus sham (Student’s t-test). C) Phactr1 and BNP mRNA levels in mechanically stretched neonatal ventricular myocytes in vitro. D) Phactr1 mRNA levels in response to p38 MAPK overexpression in neonatal ventricular myocytes in vitro (n = 5–9).*P<0.05, **P<0.01, ***P<0.001 versus control (Ctrl) or LacZ; ƗƗƗP<0.001 versus group at 4h (one-way ANOVA followed by least significance difference post hoc test). E) PHACTR1 total protein levels assessed by Western blot analyses from human heart samples (n = 2–4). **P<0.01 versus control hearts (Student’s t-test). The results are expressed as mean±SEM. Representative Western blots are shown.

Mentions: Since PHACTR1 has been associated with early-onset MI in GWAS studies [12], we first studied the effect of post-infarction myocardial remodelling on Phactr1 expression in a model of acute MI in adult rats. Both Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day in response to MI induced by ligation of LAD in rats, and they had returned to control levels at 2 weeks (Fig 1A and 1B).


The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression.

Kelloniemi A, Szabo Z, Serpi R, Näpänkangas J, Ohukainen P, Tenhunen O, Kaikkonen L, Koivisto E, Bagyura Z, Kerkelä R, Leosdottir M, Hedner T, Melander O, Ruskoaho H, Rysä J - PLoS ONE (2015)

Phactr1 mRNA and protein levels are reduced 1 day after experimental myocardial infarction (MI) in rats.A) Phactr1 mRNA levels measured by RT-PCR and B) Phactr1 total protein levels analyzed by Western blot from the LV tissue samples 1 day, 2 weeks and 4 weeks after MI (n = 6–16). Open bars represent sham and solid bars MI **P<0.01, ***P<0.001 versus sham (Student’s t-test). C) Phactr1 and BNP mRNA levels in mechanically stretched neonatal ventricular myocytes in vitro. D) Phactr1 mRNA levels in response to p38 MAPK overexpression in neonatal ventricular myocytes in vitro (n = 5–9).*P<0.05, **P<0.01, ***P<0.001 versus control (Ctrl) or LacZ; ƗƗƗP<0.001 versus group at 4h (one-way ANOVA followed by least significance difference post hoc test). E) PHACTR1 total protein levels assessed by Western blot analyses from human heart samples (n = 2–4). **P<0.01 versus control hearts (Student’s t-test). The results are expressed as mean±SEM. Representative Western blots are shown.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4476650&req=5

pone.0130502.g001: Phactr1 mRNA and protein levels are reduced 1 day after experimental myocardial infarction (MI) in rats.A) Phactr1 mRNA levels measured by RT-PCR and B) Phactr1 total protein levels analyzed by Western blot from the LV tissue samples 1 day, 2 weeks and 4 weeks after MI (n = 6–16). Open bars represent sham and solid bars MI **P<0.01, ***P<0.001 versus sham (Student’s t-test). C) Phactr1 and BNP mRNA levels in mechanically stretched neonatal ventricular myocytes in vitro. D) Phactr1 mRNA levels in response to p38 MAPK overexpression in neonatal ventricular myocytes in vitro (n = 5–9).*P<0.05, **P<0.01, ***P<0.001 versus control (Ctrl) or LacZ; ƗƗƗP<0.001 versus group at 4h (one-way ANOVA followed by least significance difference post hoc test). E) PHACTR1 total protein levels assessed by Western blot analyses from human heart samples (n = 2–4). **P<0.01 versus control hearts (Student’s t-test). The results are expressed as mean±SEM. Representative Western blots are shown.
Mentions: Since PHACTR1 has been associated with early-onset MI in GWAS studies [12], we first studied the effect of post-infarction myocardial remodelling on Phactr1 expression in a model of acute MI in adult rats. Both Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day in response to MI induced by ligation of LAD in rats, and they had returned to control levels at 2 weeks (Fig 1A and 1B).

Bottom Line: We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects.When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle.In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550).

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.

ABSTRACT
The phosphatase and actin regulator 1 (PHACTR1) locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal α-actin to cardiac α-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal α-actin to cardiac α-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550). Phactr1 seems to regulate the skeletal to cardiac α-actin isoform ratio.

No MeSH data available.


Related in: MedlinePlus