Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
Basic Res Cardiol. 2010 Nov;105(6):795-804. doi: 10.1007/s00395-010-0115-2. Epub 2010 Aug 15.
Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A.
心力衰竭的特征是肌浆网钙 ATP 酶（SERCA）表达减少和 B 型利钠肽（BNP）表达增加。本研究旨在探讨在横主动脉缩窄（TAC）小鼠模型的体内条件下，这种反向关系的因果关系。TAC 后 6 小时，左心室 SERCA-mRNA 表达显著上调 32%，但 24 小时后与假手术组无差异。TAC 后 24 小时，血清前 ANP 和 BNP 水平升高（BNP 增加 274%，p<0.01；前 ANP 增加 60%，p<0.05），但仅在 6 小时后增加（增加 182%，p<0.01）。TAC 后仅 24 小时 cGMP 水平升高（增加 307%，p<0.01），而 TAC 后 6 小时无变化。BNP 输注抑制 TAC 后 6 小时 SERCA 表达的增加。在 BNP 受体敲除动物（GC-A）中，TAC 后 24 小时 SERCA 的表达仍显著增加 35%（p<0.05），蛋白水平增加 25%（p<0.05）。MCIP 作为钙调神经磷酸酶活性的指标，在 6 小时和 24 小时后与 SERCA 平行调节。TAC 后 6 小时 MCIP-mRNA 增加 333%，但 24 小时后与假手术组无显著差异。在 GC-A-KO 小鼠中，TAC 后 24 小时与 WT 相比，MCIP-mRNA 显著增加。在 BNP 输注的小鼠中，TAC 后 6 小时与对照动物相比，MCIP 显著降低。总之，机械负荷导致 SERCA 表达上调。随后，利钠肽上调，随后抑制 SERCA 上调。升高的利钠肽可能通过激活 GC-A 抑制钙调神经磷酸酶活性来抑制 SERCA 表达。
