Downregulation of the ornithine decarboxylase/polyamine system inhibits angiotensin-induced hypertrophy of cardiomyocytes through the NO/cGMP-dependent protein kinase type-I pathway

Yan Lin, Ji-Cheng Liu, Xiao-Jie Zhang, Guang-Wei Li, Li-Na Wang, Yu-Hui Xi, Hong-Zhu Li, Ya-Jun Zhao, Chang-Qing Xu
Cellular Physiology and Biochemistry 2010, 25 (4-5): 443-50

BACKGROUND: Polyamines and nitric oxide (NO) have been involved in the pathogenesis of cardiac hypertrophy. NO can regulate cardiac ion channels by direct actions on G-proteins and adenyl cyclase. The present study was undertaken to elucidate the molecular mechanism of interactions with polyamines and NO in cardiac hypertrophy.

METHODS: Cardiaomyocyte hypertrophy was induced by angiotensinII (AngII). Hypertrophy was estimated by cell-surface area, atrial natriuretic peptide (ANP) mRNA expression, and the immunofluorescence of phalloidin. Pretreatment with alpha-difluoromethylornithine (DFMO) was done to deplete putrescine; KT5823 pretreatment was carried out to block the nitric oxide/cGMP-dependent protein kinase type-I (NO/PKG-I) pathway. Expressions of endothelial nitric oxide synthase (eNOS), PKG-I, c-fos and c-myc were analyzed by western blotting and immunofluorescence. The intracellular concentration of free calcium ([Ca2+](i)) was determined by confocal laser scanning microscopy.

RESULTS: Hypertrophy of cardiomyocytes was induced by AngII, this caused an increase in putrescine, spermidine and total polyamine pool in association with a decreased level of NO. Expressions of eNOS and PKG-I were down-regulated, [Ca2+](i) was increased, and expressions of c-Fos and c-Myc upregulated. DFMO reversed these changes induced by AngII.

CONCLUSIONS: Downregulation of polyamines inhibits cardiomyocyte hypertrophy, which is closely related to [Ca2+](i) and the NO/PKG-I pathway.

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