Fang Yu, Wang Shun, Lv Jian, Zhao Zhenyi, Guo Ningning, Wu Gang, Tong Jingjing, Wang Zhihua
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China.
Front Cardiovasc Med. 2021 Nov 1;8:736911. doi: 10.3389/fcvm.2021.736911. eCollection 2021.
Zinc dyshomeostasis has been involved in the pathogenesis of cardiac hypertrophy; however, the dynamic regulation of intracellular zinc and its downstream signaling in cardiac hypertrophy remain largely unknown. Using Zincpyr1 staining, we found a significant decrease of intracellular Zinc concentration in phenylephrine (PE)-induced hypertrophy of neonatal rat ventricular myocytes (NRVMs). We then screened SLC39 family members responsible for zinc uptake and identified Slc39a2 as the only one altered by PE treatment. Slc39a2 knockdown in NRVMs reduced the intracellular Zinc level, and exacerbated the hypertrophic responses to PE treatment. In contrast, adenovirus-mediated Slc39a2 overexpression enhanced zinc uptake and suppressed PE-induced Nppb expression. RNA sequencing analysis showed a pro-hypertrophic transcriptome reprogramming after Slc39a2 knockdown. Interestingly, the innate immune signaling pathways, including NOD signaling, TOLL-like receptor, NFκB, and IRFs, were remarkably enriched in the Slc39a2-regulated genes. Slc39a2 deficiency enhanced the phosphorylation of P65 NFκB and STAT3, and reduced the expression of IκBα. Finally, the expression of IRF7 was significantly increased by Slc39a2 knockdown, which was in turn suppressed by IRF7 knockdown. Our data demonstrate that zinc homeostasis mediated by a Slc39a2/IRF7 regulatory circuit contributes to the alteration of innate immune signaling in cardiomyocyte hypertrophy.
锌稳态失衡参与了心肌肥大的发病机制；然而，心肌肥大过程中细胞内锌的动态调节及其下游信号传导仍 largely 未知。使用 Zincpyr1 染色，我们发现在苯肾上腺素（PE）诱导的新生大鼠心室肌细胞（NRVMs）肥大中，细胞内锌浓度显著降低。然后我们筛选了负责锌摄取的 SLC39 家族成员，并确定 Slc39a2 是唯一受 PE 处理影响的成员。在 NRVMs 中敲低 Slc39a2 降低了细胞内锌水平，并加剧了对 PE 处理的肥大反应。相反，腺病毒介导的 Slc39a2 过表达增强了锌摄取并抑制了 PE 诱导的 Nppb 表达。RNA 测序分析显示，敲低 Slc39a2 后出现促肥大转录组重编程。有趣的是，包括 NOD 信号传导、Toll 样受体、NFκB 和 IRFs 在内的先天免疫信号通路在 Slc39a2 调节的基因中显著富集。Slc39a2 缺陷增强了 P65 NFκB 和 STAT3 的磷酸化，并降低了 IκBα 的表达。最后，敲低 Slc39a2 显著增加了 IRF7 的表达，而敲低 IRF7 又抑制了这种增加。我们的数据表明，由 Slc39a2/IRF7 调节回路介导的锌稳态有助于心肌细胞肥大中先天免疫信号的改变。
