Npr1-regulated gene pathways contributing to cardiac hypertrophy and fibrosis

Abstract

The natriuretic peptides, atrial (ANP) and brain natriuretic peptide (BNP) are known to suppress cardiac hypertrophy and fibrosis. Both ANP and BNP exert their bioactivities through the Npr1 receptor, and Npr1 knockout mice (Npr1K/K) exhibit marked cardiac hypertrophy and fibrosis. In this study, we investigated which genes within the hypertrophic and fibrotic pathways are influenced by the lack of Npr1 signalling. cDNA microarray and quantitative real-time PCR (RT-PCR) analyses were performed on cardiac ventricles from Npr1K/K mice. Gene expression at early and late stages during development of hypertrophy was investigated in male and female Npr1K/K mice at 8 weeks and 6 months of age. Heart weight to body weight ratios (HW:BW) were maximally increased in 8-week males (P!0 . 01), whilst HW:BW in females continued to increase progressively up to 6 months (P!0 . 01). This was despite blood pressure being similarly elevated at both the ages in male and female knockout when compared with wild-type (WT) mice (P!0 . 001). Microarray analysis identified altered gene expression at the earliest steps in the hypertrophy-signalling cascade in Npr1K/K mice, particularly calcium-calmodulin signalling and ion channels, with subsequent changes in the expression of intracellular messengers including protein kinases and transcription factors. Real-time PCR analysis confirmed significant differences in gene expression of ANP, BNP, calmodulin 1, histone deacetylase 7a (HDAC7a), protein kinase C (PKC)i, (GATA) 4, collagen 1, phospholamban and transforming growth factor-b1 in Npr1K/K mice when compared with WT (P!0 . 05). The present study implicates the calmodulin-CaMK-Hdac-Mef2 and PKC-MAPK-GATA4 pathways in Npr1 mediation of cardiac hypertrophy.

Generation and characterization of a mouse model of the metabolic syndrome: apolipoprotein E and aromatase double knockout mice

“…Mean arterial blood pressure (MAP) was calculated from systolic and diastolic readings obtained by a noninvasive, computerized tail-cuff system (ADInstruments, Dunedin, New Zealand) as previously described (10). The mice were familiarized to the procedure by being placed briefly in a restrainer and the tail cuff system over a period of 7 days, after which baseline MAP measurements were made for each animal (mean of Ն10 recordings).…”

Histone Deacetylase: A Potential Therapeutic Target for Fibrotic Disorders

“…Besides, Class II HDACs may also be involved in the pathogenesis of cardiac hypertrophy. In a study investigating the action of natriuretic peptide receptor-A-induced cardiac hypertrophy and fibrosis, Ellmers et al (2007) demonstrated that HDAC 7a mRNA expression was increased in natriuretic peptide receptor-A knockout mice at a more advanced stage, followed by increased TGF ␤1 and other structural molecules associated with cardiac fibrosis such as collagen I. Atrial interstitial fibrosis is a significant factor driving arrhythmia genesis and is highly prevalent in heart failure and cardiac hypertrophy (Verheule et al, 2004). Atrial fibrosis influences the development of atrial fibrillation, particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective in reducing atrial fibrosis and atrial fibrillation.…”

Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice

“…The ANP/NPRA system elicits natriuretic, diuretic, vasorelaxant, and antiproliferative responses, all of which contribute largely to the reduction of blood pressure and blood volume (40,49,64). Previous studies have suggested that NPRA signaling is involved not only in maintaining the arterial pressure but also in antagonizing the cardiac growth responses to hypertrophic stimuli (6,14,34). It has been shown that both external and internal stimuli regulate Npr1 (coding for GC-A/ NPRA) expression and receptor signaling, including angiotensin II (ANG II), all-trans retinoic acid (RA), vitamin D, and extracellular osmolality (1,8,16,21).…”

“…Previous studies have suggested that ANP/ NPRA signaling acts as a negative regulator of inflammation and hypertrophic growth (14,65,67,69). However, the studies on the role of ANP/NPRA in regulating the expression of hypertrophic and proinflammatory markers in vivo are limited.…”