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1 Department of Medicine, University of Pennsylvania School of Medicine, Phildadelphia, PA, USA
2 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3 Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
4 Center for Genetic Medicine, Children's National Medical Center, Washington D.C., USA
* To whom correspondence should be addressed. E-mail: jhare{at}jhmi.edu.
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 to wild-type. 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 down-regulation of fetal isoforms (
-skeletal actin and brain natriuretic peptide). Cluster analyses demonstrated that NOS1 deletion caused more pronounced changes in the myocardial transcriptome that 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.
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