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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

The effect of adenovirus-mediated Phactr1 gene delivery on LV fibrosis, apoptosis, proliferation and angiogenesis normal adult rats.A through D) fibrotic area, number of TUNEL+ cells, number of Ki-67+cells and number of capillaries in hearts at 2 weeks after gene transfer (n = 8–9). The results are expressed as mean±SEM.
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pone.0130502.g005: The effect of adenovirus-mediated Phactr1 gene delivery on LV fibrosis, apoptosis, proliferation and angiogenesis normal adult rats.A through D) fibrotic area, number of TUNEL+ cells, number of Ki-67+cells and number of capillaries in hearts at 2 weeks after gene transfer (n = 8–9). The results are expressed as mean±SEM.

Mentions: We next evaluated whether overexpression of Phactr1 would induce changes in cardiac structure and function. Interestingly, Phactr1 gene delivery did not have any influence on fibrosis as measured by staining histological sections with Masson’s trichrome, the number of apoptotic cells assessed by the TUNEL assay, cell proliferation (number of Ki-67 positive cells) or the number of capillaries (Fig 5A through 5D) and mean capillary area (data not shown). As assessed by echocardiography (data summarized in Table 2), there were also no statistically significant differences in LV ejection fraction (EF) or fractional shortening (FS) between LacZ- and Phactr1-treated groups (Fig 6A through 6C). In addition, the thickness of the interventricular septum (IVS) of the Phactr1-treated rats was similar to those of LacZ-treated group during diastole (Fig 6D). However, the IVS during systole was slightly but statistically significantly (P<0.05) thicker in the Phactr1-treated group at 3 days after Phactr1 overexpression when compared to LacZ-treated group (Fig 6E). Overall, these results indicate that Phactr1 overexpression had no major effect on LV structure and function in normal rat hearts during the 2 weeks follow-up period.


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)

The effect of adenovirus-mediated Phactr1 gene delivery on LV fibrosis, apoptosis, proliferation and angiogenesis normal adult rats.A through D) fibrotic area, number of TUNEL+ cells, number of Ki-67+cells and number of capillaries in hearts at 2 weeks after gene transfer (n = 8–9). The results are expressed as mean±SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130502.g005: The effect of adenovirus-mediated Phactr1 gene delivery on LV fibrosis, apoptosis, proliferation and angiogenesis normal adult rats.A through D) fibrotic area, number of TUNEL+ cells, number of Ki-67+cells and number of capillaries in hearts at 2 weeks after gene transfer (n = 8–9). The results are expressed as mean±SEM.
Mentions: We next evaluated whether overexpression of Phactr1 would induce changes in cardiac structure and function. Interestingly, Phactr1 gene delivery did not have any influence on fibrosis as measured by staining histological sections with Masson’s trichrome, the number of apoptotic cells assessed by the TUNEL assay, cell proliferation (number of Ki-67 positive cells) or the number of capillaries (Fig 5A through 5D) and mean capillary area (data not shown). As assessed by echocardiography (data summarized in Table 2), there were also no statistically significant differences in LV ejection fraction (EF) or fractional shortening (FS) between LacZ- and Phactr1-treated groups (Fig 6A through 6C). In addition, the thickness of the interventricular septum (IVS) of the Phactr1-treated rats was similar to those of LacZ-treated group during diastole (Fig 6D). However, the IVS during systole was slightly but statistically significantly (P<0.05) thicker in the Phactr1-treated group at 3 days after Phactr1 overexpression when compared to LacZ-treated group (Fig 6E). Overall, these results indicate that Phactr1 overexpression had no major effect on LV structure and function in normal rat hearts during the 2 weeks follow-up period.

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