2. Academic Validation
  3. The poly(ADP-ribosyl)ation of FoxO3 mediated by PARP1 participates in isoproterenol-induced cardiac hypertrophy

The poly(ADP-ribosyl)ation of FoxO3 mediated by PARP1 participates in isoproterenol-induced cardiac hypertrophy

  • Biochim Biophys Acta. 2016 Dec;1863(12):3027-3039. doi: 10.1016/j.bbamcr.2016.09.019.
Jing Lu 1,  Renwei Zhang 2,  Huiqi Hong 3,  Zuolong Yang 4,  Duanping Sun 5,  Shuya Sun 4,  Xiaolei Guo 6,  Jiantao Ye 3,  Zhuoming Li 7,  Peiqing Liu 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
  • 2 National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
  • 3 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
  • 4 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
  • 5 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China.
  • 6 Infinitus (China) Company Ltd., Guangzhou 510623, Guangdong, PR China.
  • 7 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China. Electronic address: [email protected].
  • 8 Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China; Guangdong Provincial Key Laboratory of Construction Foundation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, Guangdong, PR China. Electronic address: [email protected].
PMID: 27686254 DOI: 10.1016/j.bbamcr.2016.09.019
Abstract

The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD+-dependent synthesis of Polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs. Primary-cultured neonatal rat cardiomyocytes were incubated with isoproterenol (ISO) to induce hypertrophy, or were infected with recombinant adenovirus vectors harboring PARP1 cDNA (Ad-PARP1). Sprague-Dawley (SD) rats were treated with ISO to induce cardiac hypertrophy, or were injected with Ad-PARP1 into the anterior and posterior left ventricular walls. Cardiomyocyte surface area, the mRNA expression of hypertrophic biomarkers, echocardiography, morphometry of the hearts were measured. The PARP1 activity was tested by cellular PAR levels. Interactions of PARP1 and FoxO3 were investigated by co-immunoprecipitation and immunofluorescence technique. PARylation of FoxO3 mediated by PARP1 facilitated its phosphorylation at the T32, S252 and S314 sites, triggered its nucleus export and suppressed its transcriptional activity and target genes expression, ultimately inducing cardiac hypertrophy. Additionally, PARP1 silencing or specific inhibition by 3-Aminobenzamide (3AB) and veliparib (ABT-888) alleviated the inhibition of FoxO3 activity by ISO, thus suppressing ISO-induced cardiac hypertrophy. Our data provide the first evidence that PARP1 exacerbates cardiac hypertrophy by PARylation of FoxO3.

Keywords

Cardiac hypertrophy; FoxO3; Isoproterenol; PARP1; Poly(ADP-ribosyl)ation.

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