MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts.
MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts.
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DOI：
10.1161/jaha.116.003601
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发表时间：
2017-02-10
影响因子：
5.4
通讯作者：
Kimura T
中科院分区：
文献类型：
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作者：
Nakagawa Y;Nishikimi T;Kuwahara K;Fujishima A;Oka S;Tsutamoto T;Kinoshita H;Nakao K;Cho K;Inazumi H;Okamoto H;Nishida M;Kato T;Fukushima H;Yamashita JK;Wijnen WJ;Creemers EE;Kangawa K;Minamino N;Nakao K;Kimura T
最近的研究表明，心力衰竭患者血浆中无生物活性的脑利钠肽前体（proBNP）水平升高。这可能导致循环BNP的有效性降低，并加剧心力衰竭进展。然而，控制proBNP增加的确切机制仍不清楚。我们使用我们最近开发的高灵敏度的人proBNP测定系统来研究血浆proBNP水平升高的潜在机制。我们将53例连续住院的心力衰竭患者根据其主动脉血浆免疫反应性BNP水平分为2组。水平较高的患者表现出更严重的心力衰竭，在衰竭心脏分泌的免疫反应性BNP形式中，proBNP的比例较高，根据血浆环磷酸鸟苷水平与对数转换血浆BNP水平的比值估计，BNP的作用较弱。人proBNP的苏氨酸48和71处的糖基化通过减弱其加工促进proBNP分泌增加，GalNAc转移酶（GALNT）1和2介导了心脏人proBNP分泌的糖基化调节增加。心脏GALNT 1和2的表达受到microRNA（miR）-30的抑制，microRNA（miR）-30在健康心脏的心肌中大量表达，但在衰竭心脏中受到抑制。我们已经阐明了一种新的miR-30-GALNT 1/2轴，其失调增加了心脏分泌的无活性proBNP的比例，并在心力衰竭进展期间损害BNP的代偿作用。
Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log‐transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc‐transferase (GALNT) 1 and 2 mediated the glycosylation‐regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)‐30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. We have elucidated a novel miR‐30‐GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.