ProBNP(1-108) is resistant to degradation and activates guanylyl cyclase-A with reduced potency.
ProBNP(1-108) is resistant to degradation and activates guanylyl cyclase-A with reduced potency.
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DOI：
10.1373/clinchem.2011.169151
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发表时间：
2011-09
影响因子：
9.3
通讯作者：
Potter LR
中科院分区：
文献类型：
--
作者：
Dickey DM;Potter LR
B型利钠肽（BNP）补偿衰竭的心脏，并合成为108个残基的激素原，其被切割成32个残基的C末端最大活性肽。在心力衰竭期间，proBNP 1 -108的血清浓度超过BNP 1 -32的浓度。本研究的目的是确定proBNP 1 -108/BNP 1 -32比率增加的原因以及proBNP 1 -108是否具有生物活性。使用cGMP升高和125 I-ANP结合试验，我们测量了重组人proBNP 1 -108和人合成BNP 1 -32对单个人利钠肽受体群体的结合和激活。使用受体生物测定法，我们测量了人肾膜对重组proBNP 1 -108和BNP 1 -32的降解。ProBNP 1 -108刺激鸟苷酸环化酶-A（GC-A）接近最大活性，但效力比BNP 1 -32低13倍。ProBNP 1 -108与人GC-A的结合强度比BNP 1 -32低35倍。proBNP 1 -108和BNP 1 -32均不激活GC-B。利钠肽清除受体与proBNP 1 -108的结合强度比BNP 1 -32低3倍。proBNP 1 -108被人肾膜降解的半衰期比BNP 1 -32长2.7倍，完全降解所需的时间长6倍。BNP 1 -32和proBNP 1 -108分别通过一阶和二阶指数衰减模型最佳拟合。ProBNP 1 -108激活GC-A的效力降低，并且对降解具有抗性。proBNP 1 -108的降解减少可能有助于在充血性心力衰竭患者中观察到的血清proBNP 1 -108与BNP 1 -32的比率增加。
B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP1–108 exceed concentrations of BNP1–32. The aim of this study was to determine why the proBNP1–108/BNP1–32 ratio increases and whether proBNP1–108 is bioactive. Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP1–108 and human synthetic BNP1–32. Using receptor bioassays, we measured degradation of recombinant proBNP1–108 and BNP1–32 by human kidney membranes. ProBNP1–108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP1–32. ProBNP1–108 bound human GC-A 35-fold less tightly than BNP1–32. Neither proBNP1–108 nor BNP1–32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP1–108 3-fold less tightly than BNP1–32. The half time for degradation of proBNP1–108 by human kidney membranes was 2.7-fold longer than for BNP1–32, and the time required for complete degradation was 6-fold longer. BNP1–32 and proBNP1–108 were best fitted by first- and second-order exponential decay models, respectively. ProBNP1–108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP1–108 may contribute to the increased ratio of serum proBNP1–108 to BNP1–32 observed in patients with congestive heart failure.