title: The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression.
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.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Annina
authors.initials: A
authors.lastname: Kelloniemi
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szabo
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
authors.affiliation: Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Näpänkangas
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Pauli
authors.initials: P
authors.lastname: Ohukainen
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Tenhunen
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kaikkonen
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Koivisto
authors.affiliation: Heart Center, Semmelweis University, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagyura
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.affiliation: Lund University, Department of Clinical Sciences, Malmö, Sweden.
authors.forename: Margret
authors.initials: M
authors.lastname: Leosdottir
authors.affiliation: Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hedner
authors.affiliation: Lund University, Department of Clinical Sciences, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D008840:Microfilament Proteins; C570134:PHACTR1 protein, human; C000606152:Phactr1 protein, rat; D020033:Protein Isoforms; D012333:RNA, Messenger