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Olle Melander

Principal investigator

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

Author

  • Annina Kelloniemi
  • Zoltan Szabo
  • Raisa Serpi
  • Juha Näpänkangas
  • Pauli Ohukainen
  • Olli Tenhunen
  • Leena Kaikkonen
  • Elina Koivisto
  • Zsolt Bagyura
  • Risto Kerkelä
  • Margrét Leosdottir
  • Thomas Hedner
  • Olle Melander
  • Heikki Ruskoaho
  • Jaana Rysä

Summary, in English

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.

Department/s

  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2015

Language

English

Publication/Series

PLoS ONE

Volume

10

Issue

6

Document type

Journal article

Publisher

Public Library of Science

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Internal Medicine - Epidemiology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 1932-6203