Neuron-derived orphan receptor-1 modulates cardiac gene expression and exacerbates angiotensin II-induced cardiac hypertrophy. (4th February 2020)

• Record Type: Journal Article
• Authors: Cañes, Laia; Martí-Pàmies, Ingrid; Ballester-Servera, Carme; Herraiz-Martínez, Adela; Alonso, Judith; Galán, María; Nistal, J. Francisco; Muniesa, Pedro; Osada, Jesús; Hove-Madsen, Leif; Rodríguez, Cristina; Martínez-González, José
• Is Part Of: Clinical science. Volume 134:Number 3(2020)
• Page Start: 359
• Page End: 377
• Publication Date: 2020-02-04
• Subjects: cardiac remodelling -- hypertension -- hypertensive cardiac hypertrophy -- NOR-1; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20191014
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Hypertensive cardiac hypertrophy (HCH) is a common cause of heart failure (HF), a major public health problem worldwide. However, the molecular bases of HCH have not been completely elucidated. Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor whose role in cardiac remodelling is poorly understood. The aim of the present study was to generate a transgenic mouse over-expressing NOR-1 in the heart (TgNOR-1) and assess the impact of this gain-of-function on HCH. The CAG promoter-driven transgenesis led to viable animals that over-expressed NOR-1 in the heart, mainly in cardiomyocytes and also in cardiofibroblasts. Cardiomyocytes from TgNOR-1 exhibited an enhanced cell surface area and myosin heavy chain 7 ( Myh7 )/ Myh6 expression ratio, and increased cell shortening elicited by electric field stimulation. TgNOR-1 cardiofibroblasts expressed higher levels of myofibroblast markers than wild-type (WT) cells (α 1 skeletal muscle actin ( Acta1 ), transgelin ( Sm22α )) and were more prone to synthesise collagen and migrate. TgNOR-1 mice experienced an age-associated remodelling of the left ventricle (LV). Angiotensin II (AngII) induced the cardiac expression of NOR-1, and NOR-1 transgenesis exacerbated AngII-induced cardiac hypertrophy and fibrosis. This effect was associated with the up-regulation of hypertrophic (brain natriuretic peptide ( Bnp ), Acta1 and Myh7 ) and fibrotic markers (collagen type I α 1 chain ( Col1a1 ), Pai-1 and lysyl oxidase-like 2 ( Loxl2 )). NOR-1 transgenesis up-regulated two key genes involved in cardiac hypertrophy ( Myh7, encoding for β-myosin heavy chain (β-MHC)) and fibrosis ( Loxl2, encoding for the extracellular matrix (ECM) modifying enzyme, Loxl2 ). Interestigly, in transient transfection assays, NOR-1 drove the transcription of Myh7 and Loxl2 promoters. Our findings suggest that NOR-1 is involved in the transcriptional programme leading to HCH.