title: Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice.
abstract: The objective of the present study was to examine the genetically determined differences in the natriuretic peptide receptor-A (NPRA) gene (Npr1) copies affecting the expression of cardiac hypertrophic markers, proinflammatory mediators, and matrix metalloproteinases (MMPs) in a gene-dose-dependent manner. We determined whether stimulation of Npr1 by all-trans retinoic acid (RA) and histone deacetylase (HDAC) inhibitor sodium butyric acid (SB) suppress the expression of cardiac disease markers. In the present study, we utilized Npr1 gene-disrupted heterozygous (Npr1(+/-), 1-copy), wild-type (Npr1(+/+), 2-copy), gene-duplicated (Npr1(++/+), 3-copy) mice, which were treated intraperitoneally with RA, SB, and a combination of RA/SB, a hybrid drug (HB) for 2 wk. Untreated 1-copy mice showed significantly increased heart weight-body weight (HW/BW) ratio, blood pressure, hypertrophic markers, including beta-myosin heavy chain (β-MHC) and proto-oncogenes (c-fos and c-jun), proinflammatory mediator nuclear factor kappa B (NF-κB), and MMPs (MMP-2, MMP-9) compared with 2-copy and 3-copy mice. The heterozygous (haplotype) 1-copy mice treated with RA, SB, or HB, exhibited significant reduction in the expression of β-MHC, c-fos, c-jun, NF-κB, MMP-2, and MMP-9. In drug-treated animals, the activity and expression levels of HDAC were significantly reduced and histone acetyltransferase activity and expression levels were increased. The drug treatments significantly increased the fractional shortening and reduced the systolic and diastolic parameters of the Npr1(+/-) mice hearts. Together, the present results demonstrate that a decreased Npr1 copy number enhanced the expression of hypertrophic markers, proinflammatory mediators, and MMPs, whereas an increased Npr1 repressed the cardiac disease markers in a gene-dose-dependent manner.
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Umadevi
authors.initials: U
authors.lastname: Subramanian
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Prerna
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Indra
authors.initials: I
authors.lastname: Mani
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Isaac
authors.initials: I
authors.lastname: Kessler
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Ramu
authors.initials: R
authors.lastname: Periyasamy
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana.
authors.forename: Giri
authors.initials: G
authors.lastname: Raghavaraju
authors.affiliation: Department of Physiology, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana kpandey@tulane.edu.
authors.forename: Kailash N
authors.initials: KN
authors.lastname: Pandey
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003971:Diastole / Q000187:drug effects; D006239:Haplotypes / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006984:Hypertrophy / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D013599:Systole / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020148:Butyric Acid; D014212:Tretinoin; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
keywords: fibrosis; gene-disruption; histone acetyltransferase; histone deacetylase; hypertrophy; natriuretic peptide receptor-A