Open Accessα 1 adrenoceptor activation by norepinephrine inhibits LPS ‐induced cardiomyocyte TNF ‐α production via modulating ERK 1/2 and NF ‐κB pathway
Author(s) -
Yu Xiaohui,
Jia Baoyin,
Wang Faqiang,
Lv Xiuxiu,
Peng Xuemei,
Wang Yiyang,
Li Hongmei,
Wang Yanping,
Lu Daxiang,
Wang Huadong
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12184
Subject(s) - chemistry , mapk/erk pathway , microbiology and biotechnology , tumor necrosis factor alpha , signal transduction , endocrinology , biology , biochemistry
Cardiomyocyte tumour necrosis factor α ( TNF ‐α) production contributes to myocardial depression during sepsis. This study was designed to observe the effect of norepinephrine ( NE ) on lipopolysaccharide ( LPS )‐induced cardiomyocyte TNF ‐α expression and to further investigate the underlying mechanisms in neonatal rat cardiomyocytes and endotoxaemic mice. In cultured neonatal rat cardiomyocytes, NE inhibited LPS ‐induced TNF ‐α production in a dose‐dependent manner. α 1 ‐ adrenoceptor ( AR ) antagonist (prazosin), but neither β 1 ‐ nor β 2 ‐ AR antagonist, abrogated the inhibitory effect of NE on LPS ‐stimulated TNF ‐α production. Furthermore, phenylephrine ( PE ), an α 1 ‐ AR agonist, also suppressed LPS ‐induced TNF ‐α production. NE inhibited p38 phosphorylation and NF ‐κB activation, but enhanced extracellular signal‐regulated kinase 1/2 ( ERK 1/2) phosphorylation and c‐Fos expression in LPS ‐treated cardiomyocytes, all of which were reversed by prazosin pre‐treatment. To determine whether ERK 1/2 regulates c‐Fos expression, p38 phosphorylation, NF ‐κB activation and TNF ‐α production, cardiomyocytes were also treated with U0126, a selective ERK 1/2 inhibitor. Treatment with U0126 reversed the effects of NE on c‐Fos expression, p38 mitogen‐activated protein kinase ( MAPK ) phosphorylation and TNF ‐α production, but not NF ‐κB activation in LPS ‐challenged cardiomyocytes. In addition, pre‐treatment with SB 202190, a p38 MAPK inhibitor, partly inhibited LPS ‐induced TNF ‐α production in cardiomyocytes. In endotoxaemic mice, PE promoted myocardial ERK 1/2 phosphorylation and c‐Fos expression, inhibited p38 phosphorylation and IκBα degradation, reduced myocardial TNF ‐α production and prevented LPS ‐provoked cardiac dysfunction. Altogether, these findings indicate that activation of α 1 ‐ AR by NE suppresses LPS ‐induced cardiomyocyte TNF ‐α expression and improves cardiac dysfunction during endotoxaemia via promoting myocardial ERK phosphorylation and suppressing NF ‐κB activation.