β₁-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation.
β₁-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation.
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β1-肾上腺素受体刺激通过激活 PKA 和增强 CaMKII 和 IκBα 磷酸化促进 LPS 诱导的心肌细胞凋亡
DOI：
10.1186/s13054-015-0820-1
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发表时间：
2015-03-09
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Wang Y;Wang Y;Yang D;Yu X;Li H;Lv X;Lu D;Wang H
半胱天冬酶激活和心肌细胞凋亡与脂多糖（LPS）诱导的心肌收缩功能障碍有关。我们最近发现内源性去甲肾上腺素激活β1-肾上腺素能受体（AR）可导致内毒素血症小鼠心肌细胞凋亡。本研究进一步探讨β1-AR激活增强LPS诱导的心肌细胞凋亡的分子机制。将成年小鼠心室肌细胞暴露于LPS、多巴酚丁胺、蛋白激酶A（PKA）抑制剂或/和L型钙通道阻断剂硝苯地平。雄性BALB/c小鼠用LPS或/和β1-AR拮抗剂阿替洛尔处理。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）检测心肌细胞凋亡，并检测凋亡相关分子。β1-AR激动剂多巴酚丁胺（DOB）可促进LPS诱导的成年小鼠心室肌细胞凋亡，激活caspase-8、9和3，增加胞浆Ca ~（2+）浓度。DOB还上调LPS处理心肌细胞的TNF-α表达，降低Bcl-2水平，促进Bax向线粒体转位，线粒体膜电位降低和细胞色素c释放，以及IκBα、p38 MAPK、JNK和Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMK II）磷酸化。PKA抑制剂可阻断DOB对caspase-9活化、Bcl-2水平以及JNK和p38 MAPK磷酸化的影响，但不能阻断DOB对IκBα磷酸化、TNF-α表达和caspase-8活化的影响。硝苯地平预处理不仅能显著阻断DOB对LPS诱导的心肌细胞内Ca 2+浓度升高和CaMKII磷酸化的增强作用，而且能部分逆转DOB对LPS诱导的心肌细胞caspase-9和caspase-3/7活性的影响。此外，阿替洛尔还能抑制内毒素血症小鼠心肌TNF-α表达、JNK、p38 MAPK和CaMK Ⅱ磷酸化，增加Bcl-2表达，抑制细胞色素c释放和心肌细胞凋亡。β1-AR激活可通过激活PKA、增加CaMK Ⅱ磷酸化、增加IκBα磷酸化和TNF-α表达促进LPS诱导的心肌细胞凋亡。
Caspase activation and cardiomyocyte apoptosis have been implicated in lipopolysaccharide (LPS)-induced cardiac contractile dysfunction. We have recently demonstrated that β1-adrenoceptor (AR) activation by endogenous norepinephrine contributes to cardiomyocyte apoptosis in endotoxemic mice. Here, we further investigated the molecular mechanisms for the enhancing effect of β1-AR activation on LPS-induced cardiomyocyte apoptosis. The adult mouse ventricular myocytes were exposed to LPS, dobutamine, protein kinase A (PKA) inhibitor or/and nifedipine, an L-type Ca2+ channel blocker. Male BALB/c mice were treated with LPS or/ and β1-AR antagonist, atenolol. Cardiomyocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay and apoptosis-associated molecules were detected. LPS induced apoptosis in adult mouse ventricular myocytes, dobutamine (DOB), a β1-AR agonist, promoted apoptosis, caspase-8, 9 and 3 activation and increased cytosolic Ca2+ concentration in LPS-challenged cardiomyocytes. DOB also up-regulated TNF-α expression, decreased Bcl-2 levels, promoted Bax translocation to mitochondria, mitochondrial membrane potential loss and cytochrome c release as well as IκBα, p38 MAPK, JNK and Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in LPS-treated cardiomyocytes. PKA inhibitor abolished the effects of DOB on caspase-9 activation, Bcl-2 levels as well as JNK and p38 MAPK phosphorylation, but not on IκBα phosphorylation, TNF-α expression and caspase-8 activation in LPS-stimulated cardiomyocytes. Pretreatment with nifedipine not only significantly blocked the enhancing effects of DOB on LPS-induced elevation in cytosolic Ca2+ concentration and CaMKII phosphorylation in cardiomyocytes, but also partly reversed the effects of DOB on caspase-9 and caspase-3/7 activities in LPS-treated cardiomyocytes. Furthermore, atenolol suppressed TNF-α expression, JNK, p38 MAPK and CaMKII phosphorylation, increased Bcl-2 expression, and inhibited cytochrome c release and cardiomyocyte apoptosis in the myocardium of endotoxemic mice. β1-AR activation promotes LPS-induced apoptosis through activating PKA, increasing CaMKII phosphorylation as well as enhancing IκBα phosphorylation and TNF-α expression in cardiomyocytes.
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