RalGDS-dependent cardiomyocyte autophagy is required for load-induced ventricular hypertrophy

Oktay F. Rifki, Brian O. Bodemann, Pavan K. Battiprolu, Michael A White, Joseph A Hill

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Recent work has demonstrated that autophagy, a phylogenetically conserved, lysosome-mediated pathway of protein degradation, is a key participant in pathological cardiac remodeling. One common feature of cell growth and autophagy is membrane biogenesis and processing. The exocyst, an octomeric protein complex involved in vesicle trafficking, is implicated in numerous cellular processes, yet its role in cardiomyocyte plasticity is unknown. Here, we set out to explore the role of small G protein-dependent control of exocyst function and membrane trafficking in stress-induced cardiomyocyte remodeling and autophagy. First, we tested in cultured neonatal rat cardiomyocytes (NRCMs) two isoforms of Ral (RalA, RalB) whose actions are mediated by the exocyst. In these experiments, mTOR inhibition in response to starvation or Torin1 was preserved despite RalA or RalB knockdown; however, activation of autophagy was suppressed only in NRCMs depleted of RalB, implicating RalB as being required for mTOR-dependent cardiomyocyte autophagy. To define further the role of RalB in cardiomyocyte autophagy, we analyzed hearts from mice lacking RalGDS (Ralgds-/-), a guanine exchange factor (GEF) for the Ral family of small GTPases. RalGDS-null hearts were similar to wild-type (WT) littermates in terms of ventricular structure, contractile performance, and gene expression. However, Ralgds-/- hearts manifested a blunted growth response (p<0.05) to TAC-mediated pressure-overload stress. Ventricular chamber size and contractile performance were preserved in response to TAC in Ralgds-/- mice, and load-induced cardiomyocyte autophagy was suppressed. Interestingly, TAC-induced activation of the fetal gene program was similar in both genotypes despite the relative lack of hypertrophic growth in mutant hearts. Together, these data implicate RalGDS-mediated induction of autophagy and exocyst function as a critical feature of load-induced cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)128-138
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume59
DOIs
StateAccepted/In press - Jun 2013

Fingerprint

Autophagy
Cardiac Myocytes
Hypertrophy
Monomeric GTP-Binding Proteins
Growth
Membranes
Guanine
Cardiomegaly
Starvation
Lysosomes
Transcriptional Activation
Proteolysis
Protein Isoforms
Genotype
Gene Expression
Pressure

Keywords

  • Autophagy
  • Cardiac hypertrophy
  • Exocyst
  • Small GTPase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Molecular Biology

Cite this

RalGDS-dependent cardiomyocyte autophagy is required for load-induced ventricular hypertrophy. / Rifki, Oktay F.; Bodemann, Brian O.; Battiprolu, Pavan K.; White, Michael A; Hill, Joseph A.

In: Journal of Molecular and Cellular Cardiology, Vol. 59, 06.2013, p. 128-138.

Research output: Contribution to journalArticle

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