Absence of gp130 in dopamine β-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias
Absence of gp130 in dopamine β-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias
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DOI：
10.1152/ajpheart.00409.2009
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发表时间：
2009-09-01
影响因子：
4.8
通讯作者：
Habecker, Beth A.
中科院分区：
文献类型：
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作者：
Parrish, Diana C.;Alston, Eric N.;Habecker, Beth A.
Parrish DC，Alston en，Rohrer H，Hermes SM，Aicher SA，Nkadi P，Woodward WR，Stubbusch J，Gardner RT，Habecker BA。表达多巴胺β-羟基酶的神经元中gp130缺失会导致自主神经失衡和再灌注性心律失常增加。Am J Physiol心轮Physiol 297：H960-H967,2009。2009年7月10日首次出版；doi：10.1152/ajpheart.00409.2009。-通过糖蛋白(GP)130作用的炎性细胞因子在心肌梗死和心力衰竭后的心脏中升高。这些细胞因子是交感神经元中神经递质和神经肽产生的有力调节器，但也对心脏损伤后心肌细胞的生存至关重要。为了检测gp130细胞因子对心脏神经的影响，我们使用了gp130(DBH-Cre/lox)小鼠，这些小鼠在表达多巴胺β-羟基酶(DBH)的神经元中选择性地缺失了gp130细胞因子受体。与野生型小鼠相比，gp130(DBH-Cre/lox)小鼠的基础交感神经参数，包括去甲肾上腺素(NE)含量、酪氨酸羟化酶表达、NE转运体表达和交感神经支配密度均正常。同样，在异氟醚麻醉下测量的基础心血管参数在两种基因型中相似，包括平均动脉压、左心室收缩峰值压、dp/dt(Max)和dp/dt(Min)。然而，药物干预显示gp130(DBH-CRE/LOX)小鼠自主神经失衡，这与再灌注后室性早搏发生率增加有关。酪胺刺激NE释放和注入β-激动剂多巴酚丁胺显示肾上腺素能传递减弱，这与gp130(DBH-Cre/lox)的β受体表达减少有关。由于DBH-Cre转基因基因在副交感神经节中的发育表达，gp130被消除。在gp130(DBH-CRE/LOX)心脏，由于副交感神经驱动力降低，胆碱能传递受损，但脑干酪氨酸羟化酶免疫组织化学显示儿茶酚胺能核大体正常。因此，GP(130DBH-Cre/lox)小鼠表面上正常的基本参数掩盖了自主神经的失衡，包括交感和副交感神经传递的变化。
Parrish DC, Alston EN, Rohrer H, Hermes SM, Aicher SA, Nkadi P, Woodward WR, Stubbusch J, Gardner RT, Habecker BA. Absence of gp130 in dopamine beta-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias. Am J Physiol Heart Circ Physiol 297: H960-H967, 2009. First published July 10, 2009; doi: 10.1152/ajpheart.00409.2009.-Inflammatory cytokines that act through glycoprotein (gp) 130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130(DBH-Cre/lox) mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine beta-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130(DBH-Cre/lox) compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dt(max), and dP/dt(min). However, pharmacological interventions revealed an autonomic imbalance in gp130(DBH-Cre/lox) mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the beta-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased beta-receptor expression in gp130(DBH-Cre/lox) hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130(DBH-Cre/lox) hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp(130DBH-Cre/lox) mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.