β肾上腺素能受体与心力衰竭心肌细胞内氧浓度调控的关系

Chronic heart failure is the final common pathway of all cardiac disease. Although in clinical it is very common, it is still a treatment of difficulty and the 5 year survival rate is less than 50%. The change of β adrenergic receptor(β-AR) signal play a key role in the development of heart failure and β receptor blocker has become the first-line drug for the treatment of heart failure. Intracellular oxygen not only participate in energy generation but although play a key role in many pathophysiological process. Our previous study prompts that in normal myocardial cells not β1-AR butβ2-AR`s activation mediate intracellular oxygen concentration and β2-AR is involved in the oxygen regulation through the β2-AR-Gi-eNos pathway. β2-AR`s activation can increase the ratio of AMP/ATP, the generation of activated oxygen and the activity of prolyl hydroxylase. In heart failure, myocardial cells` β1-AR reduce and β2-AR raise relatively; the β3-AR which is rare in the normal myocardial cells is also increased. The above changes'effects on the oxygen concentration in myocardial cells and its pathophysiological significance is still not clear. This study aims to explore in heart failure how the activation of myocardial cells` β-AR regulates the intracellular oxygen concentration, to reveal the signal pathway of how the β-AR regulate the intracellular oxygen concentration and to find the pathophysiological significance of the change of intracellular oxygen concentration.

慢性心力衰竭是所有心脏疾病的最后共同通路，在临床极为常见，且仍然是治疗难点，5年生存率不到50%。β肾上腺素能受体（β-AR）信号的改变在心力衰竭的发生发展中起关键的作用，β受体阻滞剂已经成为治疗心力衰竭的一线药物；细胞内氧不仅参与能量的产生，还在许多生理病理过程中起到关键作用。我们既往的研究提示，在正常心肌细胞，β2-AR，而不是β1-AR的激活调节细胞内的氧浓度；β2-AR通过β2-AR-Gi-eNOS通路参与氧调节；β2-AR激活增加AMP/ATP的比率、活性氧的产生、脯氨酰羟化酶的活性。心力衰竭时心肌细胞β1下调而β2相对上调，在正常心肌很少表达的β3表达增加，这些变化对心肌细胞内氧浓度的影响及其病理生理意义尚不明确，本研究旨在探索心力衰竭心肌细胞β-AR激活对心肌细胞氧浓度的调节，揭示β-AR对心肌细胞内氧浓度调节的信号途径，氧浓度变化的潜在的病理生理意义。

心力衰竭是心血管疾病的终末期表现，严重危害人类的健康。心肌细胞内的氧浓度在心肌能量代谢调控中起着十分重要的作用。β肾上腺素能受体（β-ARs）介导的信号传导被认为是调控心力衰竭发生发展的重要分子机制，然而其对于心衰时心肌细胞内氧浓度的调控及其病理生理意义尚不清楚。在本项目中，我们采用苯肾上腺素处理大鼠心肌细胞，构建心力衰竭的细胞模型，发现苯肾上腺素处理后的心肌细胞内的氧浓度显著上升。分别采用β1、β2、β3这三种肾上腺素能受体的激动剂或抑制剂处理心肌细胞，发现激活或抑制β1-AR对于细胞内氧浓度无明显的调节作用，而激活β2-AR能够升高心衰细胞内的氧浓度，激活β3-AR则能够降低心衰细胞内的氧浓度，这提示β3-AR激活能够改善心衰细胞内氧代谢的水平。最后，我们还证实内皮型一氧化氮合成酶（eNOS）的激活是β3-AR改善心衰细胞氧代谢的下游分子机制。综上，本项目明确了心力衰竭时β-ARs对心肌细胞内氧浓度的调控作用，并初步揭示了β3-AR通过激活eNOS改善心衰时心肌细胞氧代谢的分子机制。