Khor Kuan Hua, Moore Tyson A, Shiels Ian A, Greer Ristan M, Arumugam Thiruma V, Mills Paul C
School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.
Faculty of Veterinary Medicine, Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia.
PLoS One. 2016 Jan 4;11(1):e0146022. doi: 10.1371/journal.pone.0146022. eCollection 2016.
Inflammation may contribute to the pathogenesis of specific cardiovascular diseases, but it is uncertain if mediators released during the inflammatory process will affect the continued efficacy of drugs used to treat clinical signs of the cardiac disease. We investigated the role of the complement 5a receptor 1 (C5aR1/CD88) in the cardiac response to inflammation or atenolol, and the effect of C5aR1 deletion in control of baseline heart rate in an anesthetized mouse model.
An initial study showed that PMX53, an antagonist of C5aR1 in normal C57BL6/J (wild type, WT) mice reduced heart rate (HR) and appeared to have a protective effect on the heart following induced sepsis. C5aR1 knockout (CD88-/-) mice had a lower HR than wild type mice, even during sham surgery. A model to assess heart rate variability (HRV) in anesthetized mice was developed to assess the effects of inhibiting the β1-adrenoreceptor (β1-AR) in a randomized crossover study design.
HR and LF Norm were constitutively lower and SDNN and HF Norm constitutively higher in the CD88-/- compared with WT mice (P< 0.001 for all outcomes). Administration of atenolol (2.5 mg/kg) reduced the HR and increased HRV (P< 0.05, respectively) in the wild type but not in the CD88-/- mice. There was no shift of the sympathovagal balance post-atenolol in either strains of mice (P> 0.05), except for the reduced LF/HF (Lower frequency/High frequency) ratio (P< 0.05) at 60 min post-atenolol, suggesting increased parasympathetic tone of the heart due to the effect of atenolol administration. The HR of the WT mice were lower post atenolol compared to the CD88-/- mice (P = 0.001) but the HRV of CD88-/- mice were significantly increased (P< 0.05), compared with WT mice.
Knockout of the C5aR1 attenuated the effect of β1-AR in the heart, suggesting an association between the β1-AR and C5aR1, although further investigation is required to determine if this is a direct or causal association.
炎症可能促成特定心血管疾病的发病机制，但炎症过程中释放的介质是否会影响用于治疗心脏病临床症状的药物的持续疗效尚不确定。我们研究了补体5a受体1（C5aR1/CD88）在心脏对炎症或阿替洛尔反应中的作用，以及C5aR1缺失对麻醉小鼠模型中基础心率控制的影响。
初步研究表明，在正常C57BL6/J（野生型，WT）小鼠中，C5aR1拮抗剂PMX53可降低心率（HR），并且在诱导脓毒症后对心脏似乎具有保护作用。即使在假手术期间，C5aR1基因敲除（CD88-/-）小鼠的心率也低于野生型小鼠。在随机交叉研究设计中，开发了一种评估麻醉小鼠心率变异性（HRV）的模型，以评估抑制β1肾上腺素能受体（β1-AR）的效果。
与WT小鼠相比，CD88-/-小鼠的HR和低频标准值（LF Norm）始终较低，而SDNN和高频标准值（HF Norm）始终较高（所有结果P<0.001）。阿替洛尔（2.5mg/kg）给药可降低野生型小鼠的HR并增加HRV（分别为P<0.05），但对CD88-/-小鼠无此作用。除了阿替洛尔给药后60分钟时低频/高频（LF/HF）比值降低（P<0.05）外，两种品系小鼠在阿替洛尔给药后交感迷走平衡均无变化（P>0.05），这表明由于阿替洛尔给药的影响，心脏的副交感神经张力增加。与CD88-/-小鼠相比，阿替洛尔给药后WT小鼠的HR较低（P = 0.001），但CD88-/-小鼠的HRV显著增加（P<0.05）。
C5aR1基因敲除减弱了β1-AR在心脏中的作用，提示β1-AR与C5aR1之间存在关联，不过仍需进一步研究以确定这是直接关联还是因果关联。
