Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway

PLoS One. 2015 Mar 31;10(3):e0122251. doi: 10.1371/journal.pone.0122251. eCollection 2015.

Abstract

Cardiac hypertrophy is an adaptive response to various physiological and pathological stimuli. Phosphoinositide-3 kinase (PI3K) is a highly conserved lipid kinase involved in physiological cardiac hypertrophy (PHH). PI3K interacting protein1 (Pik3ip1) shares homology with the p85 regulatory subunit of PI3K and is known to interact with the p110 catalytic subunit of PI3K, leading to attenuation of PI3K activity in liver and immune cells. However, the role of Pik3ip1 in the heart remains unknown. In the present study, the effects of Pik3ip1 on cardiac hypertrophy were examined. We found that the expression level of Pik3ip1 was markedly higher in cardiomyocytes than in fibroblasts. The interaction of Pik3ip1 with the p110a subunit of PI3K in the heart was identified by immunoprecipitation using neonatal rat cardiomyocytes (NRCM). Approximately 35% knockdown of Pik3ip1 was sufficient to induce myocardial hypertrophy. Pik3ip1 deficiency was shown to lead to activation of PI3K/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling pathway, increasing protein synthesis and cell size. However, adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy. Pik3ip1 was upregulated by PHH due to swimming training, but not by pathological cardiac hypertrophy (PAH) due to pressure-overload, suggesting that Pik3ip1 plays a compensatory negative role for PHH. Collectively, our results elucidate the mechanisms for the roles of Pik3ip1 in PI3K/AKT signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cardiomegaly / enzymology
  • Cardiomegaly / metabolism
  • Cardiomegaly / prevention & control*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Gene Silencing
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Physical Conditioning, Animal
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Pik3ip1 protein, mouse
  • RNA, Small Interfering
  • 1-phosphatidylinositol 3-kinase p110 subunit, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Grants and funding

This work was supported by the 2014 GIST Systems Biology Infrastructure Establishment Grant and the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2013M3A9A7046297). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.