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Circulation Research ( IF 16.5 ) Pub Date : 2022-06-23 , DOI: 10.1161/res.0000000000000557
Ruth Williams

The sinoatrial node (SAN) is responsible for triggering every natural beat of the heart over a lifetime and is comprised of both pacemaker cardiomyocytes (PCs)—responsible for the electrical impulses—and fibroblasts. The balance and arrangement of these cells is necessary for correct SAN function, but exactly how the two interact is unclear. To investigate, Chou and colleagues studied rodent PCs (derived from stem cells) cultured with and without fibroblasts. Compared with PCs cultured alone, those with fibroblasts had higher firing rates, increased glycolysis and, in line with this, elevated expression of the glycolytic enzyme aldolase C (Aldoc). This increased Aldoc expression depended on cell-to-cell contact via integrins between the fibroblasts and PCs, and blocking integrin activity reduced both Aldoc levels and PC firing frequency. Within the hearts of mice and rats, Aldoc was exclusively expressed in the SANs, the team showed, and suppressing Aldoc expression in mouse hearts lowered the animals’ heart rates. In human PCs, overexpression of Aldoc increased these cells’ firing rates suggesting similar regulatory mechanisms are present and operational. If this is indeed the case, then glycolysis- or Aldoc-based interventions might be a way to treat heart rhythm disorders, say the authors.


Transcriptome analyses tend to focus on moderately or highly expressed genes while low-abundance transcripts are often excluded. But, because changes in a gene’s expression, even at low levels, can still impact cell function, investigating low-abundance transcripts can reveal hitherto unknown genes of interest. One problem is that, at low levels, it can be tricky to distinguish genuine gene expression changes from background noise. However, this was not the case for the specially engineered heart cells used by van Gorp and colleagues. They used conditionally immortalized atrial myocytes capable of being synchronously induced to differentiate or dedifferentiate, thus reducing the noise caused by cell heterogeneity. Looking specifically at low-abundance transcripts with big expression changes, the team identified the transcript encoding kinase Sbk2, which increased 19.4 fold upon differentiation of the myocytes and decreased similarly upon dedifferentiation. In functional studies, the team found that Sbk2 is required for formation and maintenance of the cells’ sarcomeres—the contractile units of the muscle. The work thus not only adds to our understanding of atrial myocyte development but illustrates the value of studying the often overlooked transcriptional crumbs.


A combination of cholesterol accumulation in blood vessels and chronic inflammation drive the progression of atherosclerosis. Yet standard medications tackle just one of these factors—cholesterol—possibly explaining why many patients on such drugs still have vascular plaques. In considering treatments that work on both aspects of the disease, Nguyen and colleagues investigated the previously unexplored role in atherogenesis of microRNA-223 (miR-223)—a small regulatory RNA that has been shown to suppress expression of genes involved in both cholesterol uptake and inflammatory pathways in liver and immune cells. The team showed that mouse macrophages in which miR-223 had been genetically deleted exhibited increased expression of proinflammatory cytokines and reduced cholesterol efflux compared with control cells. Overexpression of the RNA had the opposite effects. Furthermore, atherosclerosis-prone mice whose hematopoietic cells lacked miR-223 had worse atherosclerosis with larger plaques and higher levels of proinflammatory cytokines than did control animals with normal miR-223. These findings highlight miR-223’s dual-pronged anti-atherogenic action and therefore indicate its potential as either a deliverable therapeutic or a drug target, say the team.



中文翻译:

在这个问题上

窦房结 (SAN) 负责触发一生中的每一次自然心跳,由起搏器心肌细胞 (PC)(负责电脉冲)和成纤维细胞组成。这些细胞的平衡和排列对于正确的 SAN 功能是必要的,但两者究竟如何相互作用尚不清楚。为了进行调查,Chou 及其同事研究了在有和没有成纤维细胞的情况下培养的啮齿动物 PC(源自干细胞)。与单独培养的 PC 相比,具有成纤维细胞的 PC 具有更高的放电率,糖酵解增加,并且与此一致,糖酵解酶醛缩酶 C (Aldoc) 的表达升高。这种增加的 Aldoc 表达依赖于成纤维细胞和 PC 之间通过整合素的细胞间接触,并且阻断整合素活性降低了 Aldoc 水平和 PC 发射频率。研究小组表明,在小鼠和大鼠的心脏中,Aldoc 仅在 SAN 中表达,抑制小鼠心脏中的 Aldoc 表达会降低动物的心率。在人类 PC 中,Aldoc 的过度表达增加了这些细胞的放电率,这表明存在类似的调节机制并发挥作用。作者说,如果情况确实如此,那么基于糖酵解或 Aldoc 的干预措施可能是治疗心律失常的一种方法。


转录组分析倾向于关注中度或高度表达的基因,而低丰度的转录本通常被排除在外。但是,因为基因表达的变化,即使是低水平的,仍然会影响细胞功能,研究低丰度的转录本可以揭示迄今为止未知的感兴趣的基因。一个问题是,在低水平下,将真正的基因表达变化与背景噪声区分开来可能很棘手。然而,van Gorp 及其同事使用的特殊工程心脏细胞并非如此。他们使用条件性永生化的心房肌细胞,能够被同步诱导分化或去分化,从而减少细胞异质性引起的噪音。研究小组专门研究了表达变化较大的低丰度转录本,确定了编码激酶 Sbk2 的转录本,在肌细胞分化时增加 19.4 倍,在去分化时同样减少。在功能研究中,研究小组发现 Sbk2 是细胞肌节(肌肉的收缩单位)的形成和维持所必需的。因此,这项工作不仅增加了我们对心房肌细胞发育的理解,而且说明了研究经常被忽视的转录屑的价值。


胆固醇在血管中的积累和慢性炎症的结合推动了动脉粥样硬化的进展。然而,标准药物只解决了这些因素之一——胆固醇——这可能解释了为什么许多服用此类药物的患者仍然有血管斑块。在考虑对疾病的两个方面都有效的治疗方法时,Nguyen 及其同事研究了 microRNA-223 (miR-223) 在动脉粥样硬化形成中的先前未探索的作用——一种小型调节 RNA,已被证明可抑制参与胆固醇摄取的基因的表达肝脏和免疫细胞中的炎症通路。研究小组表明,与对照细胞相比,基因缺失 miR-223 的小鼠巨噬细胞表现出促炎细胞因子表达增加和胆固醇流出减少。RNA的过度表达具有相反的效果。此外,与具有正常 miR-223 的对照动物相比,其造血细胞缺乏 miR-223 的易患动脉粥样硬化的小鼠的动脉粥样硬化更严重,斑块更大,促炎细胞因子水平更高。研究小组表示,这些发现突出了 miR-223 的双重抗动脉粥样硬化作用,因此表明其作为可交付治疗或药物靶点的潜力。

更新日期:2022-06-24
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