Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy

Physiol Genomics. 2003 Jun 24;14(1):25-34. doi: 10.1152/physiolgenomics.00156.2002.

Abstract

Decreased nitric oxide synthase (NOS) activity induces left ventricular hypertrophy (LVH), but the transcriptional pathways mediating this effect are unknown. We hypothesized that specific NOS isoform deletion (NOS3 or NOS1) would activate different transcriptional programs in LVH. We analyzed cardiac expression profiles (Affymetrix MG-U74A) from NOS-/- mice using robust multi-array average (RMA). Of 12,422 genes analyzed, 47 genes were differentially expressed in NOS3-/- and 67 in NOS1(-/-) hearts compared with wild type (WT). Only 16 showed similar changes in both NOS-/- strains, most notably decreased heat-shock proteins (HSP10, 40, 70, 86, 105). Hypertrophied NOS1-/- hearts had unique features, including decreased myocyte-enriched calcineurin interacting protein and paradoxical downregulation of fetal isoforms (alpha-skeletal actin and brain natriuretic peptide). Cluster analyses demonstrated that NOS1 deletion caused more pronounced changes in the myocardial transcriptome than did NOS3 deletion, despite similar cardiac phenotypes. These findings suggest that the transcriptional basis for LVH varies depending on the inciting biochemical stimulus. In addition, NOS isoforms appear to play distinct roles in modulating cardiac structure.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.
  • Validation Study

MeSH terms

  • Animals
  • Cardiomegaly / enzymology*
  • Cardiomegaly / genetics*
  • Cluster Analysis
  • Gene Expression Profiling / statistics & numerical data
  • Gene Expression Regulation / genetics*
  • Gene Expression Regulation, Enzymologic / genetics*
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nitric Oxide Synthase / deficiency*
  • Nitric Oxide Synthase / genetics*
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Polymerase Chain Reaction / methods
  • Polymerase Chain Reaction / statistics & numerical data
  • Transcription, Genetic / genetics*
  • Transcription, Genetic / physiology

Substances

  • Isoenzymes
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos1 protein, mouse
  • Nos3 protein, mouse