Neuron-derived orphan receptor-1 modulates cardiac gene expression and exacerbates angiotensin II-induced cardiac hypertrophy
Por:
Canes, L, Marti-Pamies, I, Ballester-Servera, C, Herraiz-Martinez, A, Alonso, J, Galan, M, Nistal, JF, Muniesa, P, Osada, J, Hove-Madsen, L, Rodriguez, C, Martinez-Gonzalez, J
Publicada:
1 feb 2020
Resumen:
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 (alpha 1 skeletal muscle actin (Acta1), transgelin (Sm22 alpha)) 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 alpha 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 beta-myosin heavy chain (beta-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.
Filiaciones:
Canes, L:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Marti-Pamies, I:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Ballester-Servera, C:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Herraiz-Martinez, A:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Alonso, J:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Galan, M:
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Inst Recerca Hosp Santa Creu & St Pau Programa IC, Barcelona, Spain
Nistal, JF:
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Univ Cantabria, Hosp Univ Marques Valdecilla, IDIVAL, Santander, Spain
Muniesa, P:
Univ Zaragoza, Fac Vet, Zaragoza, Spain
Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr, Madrid, Spain
Osada, J:
Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr, Madrid, Spain
Univ Zaragoza, Inst Invest Sanitaria Aragon, Fac Vet, Zaragoza, Spain
Hove-Madsen, L:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Rodriguez, C:
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Inst Recerca Hosp Santa Creu & St Pau Programa IC, Barcelona, Spain
Martinez-Gonzalez, J:
Inst Invest Biomed Barcelona IIBB CSIC, Barcelona, Spain
Inst Salud Carlos III, CIBER Enfermedades Cardiovasc, Madrid, Spain
Inst Invest Biomed St Pau IIB St Pau, Barcelona, Spain
Hybrid Gold
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