Even if a patient survives a myocardial infarction (MI), the resulting fibrosis may impair heart function to such an extent the patient ultimately succumbs to heart failure. With the aim of informing fibrosis prevention and treatment strategies, Ni and colleagues searched for genes involved in the process. They performed a transcriptome analysis of heart tissue from rats that had or had not been subjected to MI and found that the gene for flavin-containing monooxygenase 2 (FMO2) was dramatically down-regulated in the MI hearts. Similarly, decreased FMO2 expression was observed in mouse, monkey and human heart tissue after MI. Suppression of FMO2 expression in the hearts of live rats prompted increased myocardial fibrosis and reduced heart function, while ramping up cardiac FMO2 expression immediately after MI reduced scarring and improved function in rodent and monkey hearts compared with controls. The team went on to determine the mechanism of FMO2’s anti-fibrotic effect, showing it interacted with the cytochrome CYP2J3 and disrupted SMAD signaling, which ultimately suppressed fibrotic genes. They also showed that such fibrotic genes could be suppressed in human cardiac scar fibroblasts by boosting FMO2–a strategy that could potentially be adapted clinically to reduce the risk of heart failure.

Cardiomyopathy is a common complication of chronic kidney disease (CKD), but what leads to the heart damage is not fully understood. CKD can exacerbate or induce high blood pressure, which in turn can damage the heart. However, signs of cardiomyopathy can occur at early stages of CKD when blood pressure might still be relatively normal. Thomas and colleagues suspected that signal regulatory protein α (SIRPα) might be an alternative trigger. Levels of SIRPα are elevated in the skeletal muscles of CKD model mice where the protein disrupts insulin signaling and causes muscle atrophy. Sure enough, the team’s new work shows SIRPα causes similar problems in the heart. SIRPα levels were elevated in the hearts of CKD mice and were correlated with impaired insulin/IGF1 receptor signaling, myocardial dysfunction and fibrosis. Furthermore, suppression of SIRPα in these CKD mice prevented myocardial fibrosis and improved heart function. Using biochemical analyses, the team revealed that SIRPα exerts its effect through direct interaction with, and inhibition of, the IGF1 receptor. Together the results suggest that SIRPα could be not only a marker of insulin resistance and cardiomyopathy in CKD, but also a clinical target for treating or preventing this heart damage.

While hydrogen sulfide (H₂S) is poisonous to humans if inhaled, evidence suggests in its endogenously produced form it protects the heart from myocardial infarction, arrhythmia and other heart-damaging conditions. One of the cellular H₂S-producing enzymes is 3-mercaptopyruvate sulfurtransferase (3-MST) and, after a heart injury, mice lacking this enzyme have exacerbated cardiac dysfunction and severe exercise intolerance compared with control animals. To understand how 3-MST might protect the heart, Li and colleagues performed a metabolomic screen in mice with and without 3-MST and found those lacking the enzyme had defects in their catabolism of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Importantly, pharmacologically reducing the levels of these BCAAs attenuated the effects of injury in the hearts of 3-MST-lacking mice and control animals. It is not clear how 3-MST regulates BCAA catabolism, but the team’s finding that heart tissue from patients with end-stage heart failure has unusually low levels of 3-MST, suggests it would be worthwhile examining BCAA catabolism in such tissue too. If the results hold true, then modulation of 3-MST, or indeed BCAAs or H₂S, could be investigated as potential treatment strategies.

即使患者在心肌梗塞 (MI) 中幸存下来，由此产生的纤维化也可能会损害心脏功能，直至患者最终死于心力衰竭。为了为纤维化预防和治疗策略提供信息，Ni 及其同事搜索了参与该过程的基因。他们对患有或未患 MI 的大鼠的心脏组织进行了转录组分析，发现含黄素的单加氧酶 2 (FMO2) 基因在 MI 心脏中显着下调。同样，在 MI 后，在小鼠、猴子和人类心脏组织中观察到 FMO2 表达降低。抑制活大鼠心脏中 FMO2 的表达会导致心肌纤维化增加和心脏功能降低，与对照组相比，MI 后立即增加心脏 FMO2 表达可减少啮齿动物和猴子心脏的瘢痕形成并改善功能。该团队继续确定 FMO2 抗纤维化作用的机制，表明它与细胞色素 CYP2J3 相互作用并破坏 SMAD 信号传导，最终抑制纤维化基因。他们还表明，可以通过增强 FMO2 来抑制人类心脏瘢痕成纤维细胞中的此类纤维化基因——这种策略可能在临床上适用以降低心力衰竭的风险。

心肌病是慢性肾脏病 (CKD) 的常见并发症，但导致心脏损伤的原因尚不完全清楚。CKD 会加剧或诱发高血压，进而损害心脏。然而，心肌病的迹象可能出现在 CKD 的早期阶段，此时血压可能仍相对正常。Thomas 及其同事怀疑信号调节蛋白 α (SIRPα) 可能是另一种触发因素。CKD 模型小鼠骨骼肌中的 SIRPα 水平升高，该蛋白质会破坏胰岛素信号传导并导致肌肉萎缩。果然，该团队的新工作表明 SIRPα 在心脏中引起了类似的问题。CKD 小鼠心脏中 SIRPα 水平升高，并与胰岛素/IGF1 受体信号传导受损、心肌功能障碍和纤维化相关。此外，在这些 CKD 小鼠中抑制 SIRPα 可预防心肌纤维化并改善心脏功能。通过生化分析，研究小组发现 SIRPα 通过与 IGF1 受体的直接相互作用和抑制来发挥作用。总之，这些结果表明 SIRPα 不仅可以作为 CKD 中胰岛素抵抗和心肌病的标志物，而且可以作为治疗或预防这种心脏损伤的临床靶点。

虽然人体吸入硫化氢 (H ₂ S) 是有毒的，但有证据表明，它内源性产生的形式可以保护心脏免受心肌梗塞、心律失常和其他心脏损伤性疾病的影响。细胞 H _2之一产生 S 的酶是 3-巯基丙酮酸硫转移酶 (3-MST)，在心脏损伤后，与对照动物相比，缺乏这种酶的小鼠会加剧心脏功能障碍和严重的运动不耐受。为了了解 3-MST 如何保护心脏，Li 及其同事在有和没有 3-MST 的小鼠中进行了代谢组学筛选，发现缺乏该酶的小鼠在支链氨基酸 (BCAA) 亮氨酸、异亮氨酸的分解代谢中存在缺陷和缬氨酸。重要的是，在药理学上降低这些 BCAAs 的水平会减弱缺乏 3-MST 的小鼠和对照动物心脏损伤的影响。目前尚不清楚 3-MST 如何调节 BCAA 分解代谢，但研究小组发现终末期心力衰竭患者的心脏组织中 3-MST 水平异常低，表明在这种组织中检查 BCAA 分解代谢也是值得的。如果结果成立，则调制 3-MST，或者实际上是 BCAAs 或 H₂ S，可以作为潜在的治疗策略进行研究。