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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

Effect of Phactr1 gene transfer on the expression of contractility protein genes in normal adult rat heart.Skeletal α-actin (skα-A), cardiac α-actin (caα-A), β-myosin heavy chain (β-MHC) and α-myosin heavy chain (α-MHC) mRNA levels were measured by RT-PCR from LV apex tissue samples 3 days (A and B), 1 week (C and D) and 2 weeks (E and F) after Phactr1 gene transfer. Open bars represent LacZ and solid bars Phactr1. The results are expressed as mean±SEM (n = 8–9).*P< 0.05, **P<0.01 versus LacZ (Student’s t-test).
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pone.0130502.g003: Effect of Phactr1 gene transfer on the expression of contractility protein genes in normal adult rat heart.Skeletal α-actin (skα-A), cardiac α-actin (caα-A), β-myosin heavy chain (β-MHC) and α-myosin heavy chain (α-MHC) mRNA levels were measured by RT-PCR from LV apex tissue samples 3 days (A and B), 1 week (C and D) and 2 weeks (E and F) after Phactr1 gene transfer. Open bars represent LacZ and solid bars Phactr1. The results are expressed as mean±SEM (n = 8–9).*P< 0.05, **P<0.01 versus LacZ (Student’s t-test).

Mentions: Since Phactrs are a family of actin regulatory proteins and MI activates the fetal gene program, we next analyzed changes in LV contractile protein gene expression. Strikingly, Phactr1 overexpression caused the skeletal α-actin to cardiac α-actin ratio to be significantly higher (1.5-fold, P<0.05) 3 days after Phactr1 gene delivery but 40% lower (P<0.05) at 2 weeks (Fig 3A, 3C and 3E), whereas the change in β-myosin heavy chain to α-myosin heavy chain ratio was not statistically significant (Fig 3B, 3D and 3F). Furthermore, the mRNA levels for ANP, BNP, Serca2 and phospholamban (PLB) remained unchanged, with the exception that ANP mRNA levels were lower in Phactr1-treated hearts than in the LacZ-treated hearts at 2 weeks (Fig 4A through 4C).


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)

Effect of Phactr1 gene transfer on the expression of contractility protein genes in normal adult rat heart.Skeletal α-actin (skα-A), cardiac α-actin (caα-A), β-myosin heavy chain (β-MHC) and α-myosin heavy chain (α-MHC) mRNA levels were measured by RT-PCR from LV apex tissue samples 3 days (A and B), 1 week (C and D) and 2 weeks (E and F) after Phactr1 gene transfer. Open bars represent LacZ and solid bars Phactr1. The results are expressed as mean±SEM (n = 8–9).*P< 0.05, **P<0.01 versus LacZ (Student’s t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476650&req=5

pone.0130502.g003: Effect of Phactr1 gene transfer on the expression of contractility protein genes in normal adult rat heart.Skeletal α-actin (skα-A), cardiac α-actin (caα-A), β-myosin heavy chain (β-MHC) and α-myosin heavy chain (α-MHC) mRNA levels were measured by RT-PCR from LV apex tissue samples 3 days (A and B), 1 week (C and D) and 2 weeks (E and F) after Phactr1 gene transfer. Open bars represent LacZ and solid bars Phactr1. The results are expressed as mean±SEM (n = 8–9).*P< 0.05, **P<0.01 versus LacZ (Student’s t-test).
Mentions: Since Phactrs are a family of actin regulatory proteins and MI activates the fetal gene program, we next analyzed changes in LV contractile protein gene expression. Strikingly, Phactr1 overexpression caused the skeletal α-actin to cardiac α-actin ratio to be significantly higher (1.5-fold, P<0.05) 3 days after Phactr1 gene delivery but 40% lower (P<0.05) at 2 weeks (Fig 3A, 3C and 3E), whereas the change in β-myosin heavy chain to α-myosin heavy chain ratio was not statistically significant (Fig 3B, 3D and 3F). Furthermore, the mRNA levels for ANP, BNP, Serca2 and phospholamban (PLB) remained unchanged, with the exception that ANP mRNA levels were lower in Phactr1-treated hearts than in the LacZ-treated hearts at 2 weeks (Fig 4A through 4C).

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