Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cell Death Dis. 2018 Jun 7;9(6):694. doi: 10.1038/s41419-018-0723-6.
Histamine is a widely distributed biogenic amine involved in the regulation of an array of biological processes. Serum histamine level is markedly elevated in the early stages of acute myocardial infarction, whereas the role it plays remains unclear. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine production, and cardiac injury is significantly aggravated in HDC knockout mice (HDC), in which histamine is deficient. We also observed that autophagy was highly activated in cardiomyocytes of HDC mice post acute myocardial infarction (AMI), which was abolished by compensation of exogenous histamine. The in vivo and in vitro results showed that acting through histamine 1 receptor, histamine increased miR-206 and miR-216b, which worked in concert to target to Atg13, resulting in the reduction of autophagy activation under hypoxia and AMI condition. Further study revealed that Atg13 interacted with FADD to promote the activation of caspase-8 and cell apoptosis. Taken together, these data unveil a novel intracellular signaling pathway involved in histamine regulating myocardial autophagy and apoptosis under hypoxia and AMI condition, which might help to more comprehensively evaluate the usage of histamine receptor antagonists and to develop new therapeutic targets for myocardial infarction.
组胺是一种广泛分布的生物胺，参与调节一系列生物过程。在急性心肌梗死的早期，血清组胺水平明显升高，但其作用尚不清楚。组氨酸脱羧酶（HDC）是唯一负责产生组胺的酶，在 HDC 敲除小鼠（HDC）中，由于缺乏组胺，心脏损伤明显加重。我们还观察到，在急性心肌梗死（AMI）后 HDC 小鼠的心肌细胞中自噬被高度激活，而外源性组胺的补偿则消除了这种激活。体内和体外的结果表明，组胺通过组胺 1 受体作用，增加了 miR-206 和 miR-216b，它们协同作用于 Atg13，从而减少了低氧和 AMI 条件下自噬的激活。进一步的研究表明，Atg13 与 FADD 相互作用，促进了 caspase-8 的激活和细胞凋亡。总之，这些数据揭示了一种新的细胞内信号通路，涉及组胺在低氧和 AMI 条件下调节心肌自噬和凋亡，这可能有助于更全面地评估组胺受体拮抗剂的使用，并为心肌梗死开发新的治疗靶点。
