Inherited hypertrophic cardiomyopathy (HCM), characterized by thickening and dysfunction of the heart muscle, is the most common genetic heart disorder. Mutations causing HCM often affect a single gene, such as the myosin heavy chain (MHC) gene, and as such have the potential to be corrected by gene editing style approaches. Not all editing techniques are the same, however, with some potentially introducing unwanted insertions or deletions of nucleotides (indels) at the target site. Ma and colleagues wondered whether base editing—in which a single nucleotide basepair is corrected and which typically doesn’t lead to indels—might be a safer approach. The team created a base-editor system to convert an HCM-causing A-T basepair into the wildtype G-C at a single point in the mouse Mhc6 gene. Transfection of the base-editing system into single-cell zygotes resulted in a correction rate of approximately 60-70 percent and, after transfer of the corrected embryos into surrogate females, prevented HCM in the postnatal animals. The team also performed base editing on mouse embryos in utero, achieving a 25 percent gene correction rate. The approach did not cause detectable indels or off-target editing, the team showed, suggesting it might have potential for development as a clinical tool.

After a myocardial infarction, the injured heart muscle is largely unable to regenerate and instead forms a dysfunctional scar that can ultimately lead to heart failure. Cardiomyocyte-specific inhibition of the kinase MST1—shown to boost repair and regeneration in other organs—can prevent infarction-induced death of these cells and preserve heart function, suggesting it may have clinical utility. However, MST1 also has anti-inflammatory properties in macrophages. Its inhibition in those cells may thus delay inflammation resolution after infarction and impair proper healing. Liu and colleagues have now examined mice lacking MST1 in macrophages and found that, sure enough, after myocardial infarction the inflammatory mediator leukotriene B4 was upregulated in macrophages and the animals’ heart function was reduced compared to that of wildtype controls. Importantly, blocking the action of leukotriene B4 in mice reduced infarction injuries in the hearts of MST1-lacking animals and enhanced repair in the injured hearts of wildtype animals given an MST1 inhibitor. The results suggest that, if MST1 inhibition is used as a future post-infarction regenerative therapy, then leukotriene B4 blockade may prevent its inflammatory side-effects.

Restoring blood flow to ischemic heart muscle after a myocardial infarction is critical for salvaging muscle function, but can itself cause damage—so-called reperfusion injury. The generation of reactive oxygen species (ROS) and loss of nitric oxide (NO) both contribute to such injury, and the situation is exacerbated by the NO-producing enzyme, endothelial NO synthase (eNOS), producing damaging superoxide anions instead of NO. This switch in eNOS function is caused by glutathionylation of the enzyme (SG-eNOS), but how long the malfunction lasts and how it is rectified is unclear. Subramani and colleagues show that in human endothelial cells exposed to several hours of hypoxia followed by reoxygenation, the level of SG-eNOS steadily increases until, at 16 hours, it decreases sharply. By blocking several different cellular degradation pathways, the team discovered that this decrease in SG-eNOS was due to chaperone-mediated autophagy, with chaperone protein HSC70 being responsible for SG-eNOS destruction. Importantly, the team went on to show that pharmacological deglutathionylation of eNOS in mice promoted NO production and reduced reperfusion injury, suggesting this approach may be of clinical benefit after a myocardial infarction.

以心肌增厚和功能障碍为特征的遗传性肥厚型心肌病 (HCM) 是最常见的遗传性心脏病。导致 HCM 的突变通常会影响单个基因，例如肌球蛋白重链 (MHC) 基因，因此有可能通过基因编辑方式进行纠正。然而，并非所有编辑技术都相同，其中一些技术可能会在目标位点引入不需要的核苷酸插入或缺失（插入缺失）。Ma 及其同事想知道碱基编辑（其中纠正单个核苷酸碱基对并且通常不会导致插入缺失）是否可能是一种更安全的方法。该团队创建了一个碱基编辑器系统，以在小鼠Mhc6的单个点将导致 HCM 的 AT 碱基对转化为野生型 GC基因。将碱基编辑系统转染到单细胞受精卵中导致了大约 60-70% 的校正率，并且在将校正的胚胎转移到代孕雌性后，可以防止出生后动物的 HCM。该团队还在子宫内对小鼠胚胎进行了基础编辑，实现了 25% 的基因校正率。该团队表示，该方法不会导致可检测的插入缺失或脱靶编辑，这表明它可能具有作为临床工具开发的潜力。

心肌梗塞后，受损的心肌在很大程度上无法再生，而是形成功能失调的疤痕，最终导致心力衰竭。心肌细胞特异性抑制 MST1 激酶 - 显示可促进其他器官的修复和再生 - 可以防止这些细胞的梗塞诱导死亡并保护心脏功能，表明它可能具有临床效用。然而，MST1 在巨噬细胞中也具有抗炎特性。因此，它对这些细胞的抑制可能会延迟梗塞后炎症消退并损害正常愈合。Liu 及其同事现在检查了巨噬细胞中缺乏 MST1 的小鼠，并发现，果然，心肌梗塞后，巨噬细胞中的炎症介质白三烯 B4 上调，与野生型对照相比，动物的心脏功能降低。重要的是，阻断白三烯 B4 在小鼠中的作用可减少缺乏 MST1 的动物心脏的梗塞损伤，并增强给予 MST1 抑制剂的野生型动物受损心脏的修复。结果表明，如果 MST1 抑制被用作未来的梗塞后再生疗法，那么白三烯 B4 阻断可能会防止其炎症副作用。

心肌梗塞后恢复缺血心肌的血流对于挽救肌肉功能至关重要，但本身会造成损伤——所谓的再灌注损伤。活性氧 (ROS) 的产生和一氧化氮 (NO) 的损失都会导致这种损伤，并且这种情况会因产生 NO 的酶、内皮 NO 合酶 (eNOS) 而加剧，产生破坏性的超氧阴离子而不是 NO。eNOS 功能的这种转变是由酶 (SG-eNOS) 的谷胱甘肽化引起的，但故障持续多长时间以及如何纠正尚不清楚。Subramani 及其同事表明，在暴露于缺氧数小时然后再充氧的人类内皮细胞中，SG-eNOS 的水平稳步上升，直到 16 小时后急剧下降。通过阻断几种不同的细胞降解途径，研究小组发现，SG-eNOS 的这种减少是由于伴侣蛋白介导的自噬，伴侣蛋白 HSC70 负责 SG-eNOS 的破坏。重要的是，该团队继续表明，小鼠 eNOS 的药理学脱谷胱甘肽化促进了 NO 的产生并减少了再灌注损伤，表明这种方法可能对心肌梗塞后的临床有益。