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.
Highlights
Heart failure (HF) is one of the most common cardiovascular diseases with high morbidity and mortality in the Western world [1]
Since phosphatase and actin regulator 1 (PHACTR1) has been associated with early-onset myocardial infarction (MI) in genome-wide association studies (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
Summary
Heart failure (HF) is one of the most common cardiovascular diseases with high morbidity and mortality in the Western world [1]. One fundamental feature of the hemodynamically stressed, failing heart is the appearance of the fetal gene program [4]. There is a reprogramming of cardiac gene expression e.g.up-regulation of atrial and brain natriuretic peptides (ANP and BNP) [7], and a switch to fetal isoforms of contractile proteins such as cardiac α-actin being substituted by skeletal α-actin and α-myosin heavy chain by β-myosin heavy chain [4,8]. The genes coding for skeletal α-actin and β-myosin heavy chain are silent in the adult heart but their expression is reactivated in response to pathological stress [4,6,9]. An analysis of the mechanisms that regulate the expression of fetal cardiac genes can provide new insights into the development of cardiac hypertrophy and heart failure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
