Innate Immune Response Group, Instituto de Investigación La Paz, La Paz University Hospital, Madrid, Spain.
Department of Cardiology, University Hospital Ramón y Cajal/University Francisco de Vitoria, Madrid, Spain.
J Am Coll Cardiol. 2017 Jan 31;69(4):423-433. doi: 10.1016/j.jacc.2016.10.073.
Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases.
This study evaluated the role of NOD1 in HF progression.
NOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1 mice (Nod1-PMI).
The NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1-PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1-PMI mice was associated with prevention of Ca dynamic impairment linked to HF, including smaller and longer intracellular Ca concentration transients and a lesser sarcoplasmic reticulum Ca load due to a down-regulation of the sarcoplasmic reticulum Ca-adenosine triphosphatase pump and by augmented levels of the Na/Ca exchanger. Increased diastolic Ca release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1-PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca mishandling in wt-PMI mice. Nod1-PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-PMI mice.
NOD1 modulated intracellular Ca mishandling in HF, emerging as a new target for HF therapy.
心力衰竭（HF）是一种与适应性先天免疫系统反应相关的复杂综合征，导致有害的心脏重构。然而，这种综合征的潜在机制还不太清楚。核苷酸结合寡聚化结构域蛋白 1（NOD1）是一种新发现的先天免疫传感器，参与心血管疾病。
本研究评估了 NOD1 在 HF 进展中的作用。
研究了 NOD1 在人心力衰竭和心肌梗死后心力衰竭（PMI）模型中的作用，评估了野生型（wt-PMI）和 Nod1 小鼠（Nod1-PMI）中的 NOD1。
NOD1 通路在人心力衰竭和鼠心力衰竭中上调。与 wt-PMI 相比，Nod1-PMI 小鼠的心脏功能更好，结构重构减弱。Nod1-PMI 小鼠心脏功能的改善与 HF 相关的 Ca 动力学损伤的预防有关，包括更小和更长的细胞内 Ca 浓度瞬变和由于肌浆网 Ca-三磷酸腺苷酶泵下调和 Na/Ca 交换器水平升高导致的肌浆网 Ca 负荷减小。wt-PMI 心肌细胞中舒张期 Ca 释放增加与肌浆网 Ca 释放通道蛋白的过度磷酸化有关，而 Nod1-PMI 心肌细胞中的这种磷酸化减弱。NOD1 的药理学阻断也防止了 wt-PMI 小鼠的 Ca 处理不当。Nod1-PMI 小鼠在给予异丙肾上腺素后心律失常和死亡率明显降低。这些作用与异常收缩期 Ca 释放减少有关，并且在 Nod1-PMI 小鼠中，异丙肾上腺素给药时肌浆网 Ca 释放通道蛋白的过度磷酸化得到预防。
NOD1 调节 HF 中的细胞内 Ca 处理不当，成为 HF 治疗的新靶点。
