Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression
Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression
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DOI：
10.1161/circulationaha.105.608828
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发表时间：
2006-06-13
期刊：
影响因子：
37.8
通讯作者：
Hasenfuss, Gerd
中科院分区：
文献类型：
--
作者：
Koegler, Harald;Schott, Peter;Hasenfuss, Gerd
背景 - 在心力衰竭 (HF) 中，心室心肌表达脑钠尿肽 (BNP)。尽管血清水平升高与不良预后相关，但 BNP 的释放由于其抗肥厚、血管舒张和利尿特性而被认为是有益的。然而，有证据表明 BNP 介导的信号传导可能对心脏重塑产生不利影响，进一步损害钙稳态。方法和结果 - 我们研究了 BNP 对前负荷依赖性心肌肌浆网 Ca2+ ATP 酶 (SERCA2a) 表达的影响。在拉伸至高预负荷并等渗缩短超过 6 小时的兔离体肌肉条中，与未负荷的制剂相比，SERCA/磷酸甘油醛脱氢酶 mRNA 比率提高了 168%（n = 8）（n = 8；P < 0.001）。重组人 BNP 在终末期心力衰竭患者中常见的浓度 (350 pg/mL) 通过拉伸消除了 SERCA 上调（n = 9；与不含 BNP 的相比，P < 0.0001）。环鸟苷 3', 5' 单磷酸 (cGMP)-磷酸二酯酶-5 的抑制模拟了这种效应，而 cGMP 依赖性蛋白激酶的抑制则在重组人 BNP 存在的情况下恢复了前负荷依赖性 SERCA 上调。此外，在接受心脏移植的人类终末期心力衰竭患者 (n = 15) 的心肌中，BNP 表达与 SERCA 水平呈负相关。此外，在 23 名接受左心室辅助装置治疗的患者中，下调 BNP 的患者的 SERCA2a 显着恢复。结论 - 我们的数据表明预负荷刺激 SERCA 表达。 BNP 通过鸟苷酸环化酶 A、cGMP 和 cGMP 依赖性蛋白激酶拮抗这一机制。 BNP 解偶联前负荷依赖性 SERCA 表达的这种新作用可能会对心力衰竭患者的收缩力产生不利影响。
Background - In heart failure ( HF), ventricular myocardium expresses brain natriuretic peptide ( BNP). Despite the association of elevated serum levels with poor prognosis, BNP release is considered beneficial because of its antihypertrophic, vasodilating, and diuretic properties. However, there is evidence that BNP-mediated signaling may adversely influence cardiac remodeling, with further impairment of calcium homeostasis.Methods and Results - We studied the effects of BNP on preload-dependent myocardial sarcoplasmic reticulum Ca2+ ATPase ( SERCA2a) expression. In rabbit isolated muscle strips stretched to high preload and shortening isotonically over 6 hours, the SERCA/glyceraldehyde phosphate dehydrogenase mRNA ratio was enhanced by 168% ( n = 8) compared with unloaded preparations ( n = 8; P < 0.001). Recombinant human BNP at a concentration typically found in end-stage HF patients ( 350 pg/mL) abolished SERCA upregulation by stretch ( n = 9; P < 0.0001 versus BNP free). Inhibition of cyclic guanosine 3', 5' monophosphate ( cGMP)-phosphodiesterase-5 mimicked this effect, whereas inhibition of cGMP-dependent protein kinase restored preload-dependent SERCA upregulation in the presence of recombinant human BNP. Furthermore, in myocardium from human end-stage HF patients undergoing cardiac transplantation ( n = 15), BNP expression was inversely correlated with SERCA levels. Moreover, among 23 patients treated with left ventricular assist devices, significant SERCA2a recovery occurred in those downregulating BNP.Conclusions - Our data indicate that preload stimulates SERCA expression. BNP antagonizes this mechanism via guanylyl cyclase-A, cGMP, and cGMP-dependent protein kinase. This novel action of BNP to uncouple preload-dependent SERCA expression may adversely affect contractility in patients with HF.