Neuron-derived orphan receptor-1 modulates cardiac gene expression and exacerbates angiotensin II-induced cardiac hypertrophy

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