Chronic Contractile Dysfunction without Hypertrophy Does Not Provoke a Compensatory Transcriptional Response in Mouse Hearts

PLoS One. 2016 Jun 30;11(6):e0158317. doi: 10.1371/journal.pone.0158317. eCollection 2016.

Abstract

Diseased myocardium from humans and experimental animal models shows heightened expression and activity of a specific subtype of phospholipase C (PLC), the splice variant PLCβ1b. Previous studies from our group showed that increasing PLCβ1b expression in adult mouse hearts by viral transduction was sufficient to cause sustained contractile dysfunction of rapid onset, which was maintained indefinitely in the absence of other pathological changes in the myocardium. We hypothesized that impaired contractility alone would be sufficient to induce a compensatory transcriptional response. Unbiased, comprehensive mRNA-sequencing was performed on 6 biological replicates of rAAV6-treated blank, PLCβ1b and PLCβ1a (closely related but inactive splice variant) hearts 8 weeks after injection, when reduced contractility was manifest in PLCβ1b hearts without evidence of induced hypertrophy. Expression of PLCβ1b resulted in expression changes in only 9 genes at FDR<0.1 when compared with control and these genes appeared unrelated to contractility. Importantly, PLCβ1a caused similar mild expression changes to PLCβ1b, despite a complete lack of effect of this isoform on cardiac contractility. We conclude that contractile depression caused by PLCβ1b activation is largely independent of changes in the transcriptome, and thus that lowered contractility is not sufficient in itself to provoke measurable transcriptomic alterations. In addition, our data stress the importance of a stringent control group to filter out transcriptional changes unrelated to cardiac function.

MeSH terms

  • Animals
  • Dependovirus / genetics
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation
  • Heart / physiopathology*
  • Mice
  • Myocardial Contraction
  • Myocardium / metabolism
  • Phospholipase C beta / genetics*
  • Phospholipase C beta / metabolism
  • RNA Splice Sites
  • Sequence Analysis, RNA / methods*
  • Signal Transduction
  • Transcription, Genetic

Substances

  • RNA Splice Sites
  • Phospholipase C beta
  • Plcb1 protein, mouse

Grant support

This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC) #1002328, #10007712, #1022678. EAW and JRM are Fellows of the NHMRC #586621, #1078985, respectively. Support was received from the Victorian Government's Operational Infrastructure Support Program and from a Commercialization Grant provided by the Baker IDI Heart and Diabetes Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.