High blood pressure is a leading cause of cardiac hypertrophy—an increase in the heart’s muscle mass. In the short term, this growth helps the heart deal with the pressure overload but, if the pressure persists, pathological hypertrophy occurs, including fibrosis and stiffening of the muscle, and can lead to heart failure. It has been suggested that infiltrating macrophages may tip the scales towards pathology despite resident macrophages promoting tissue repair. To examine the roles of macrophages in hypertrophy more closely, Revelo and colleagues specifically depleted heart-resident macrophages in mice with a carefully designed antibody treatment that left circulating macrophages unaffected. They discovered that while the test and control mice responded similarly to heart pressure overload for the first week, in the long-term, the test mice exhibited accelerated decline in heart function and more severe fibrosis. Furthermore, mice whose circulating macrophages were also depleted were protected from this fibrosis. This suggests that recruited macrophages do indeed counteract the actions of resident ones and thereby promote pathology. Understanding the role of immune cells in heart failure will ultimately inform future therapies, say the team.

People with obesity or diabetes are at increased risk of developing cardiomyopathy which can eventually lead to heart failure. One of the major pathological features of obesity-related cardiomyopathy at the cellular level is a decrease in mitochondrial function, likely explained by a concurrent decrease in canonical mitophagy—a process whereby dysfunctional mitochondrial are degraded. An alternative mitophagy mechanism mediated by the factors Ulk1 and Rab9 has recently been discovered, however, and now Tong and colleagues show that this alternative version is actually upregulated steadily over 24 weeks in mice given a chronic high fat diet. Canonical mitophagy, by contrast, ceased after approximately two months. The team showed that suppressing the alternative mitophagy—either by knockout of Ulk1 or expression of a Rab9 loss-of-function mutant—further exacerbated the high-fat diet induced cardiac dysfunction, while over-expression of Rab9 in mouse hearts increased the alternative mitophagy and protected the animals from cardiac dysfunction. Together the results suggest that pharmacologically boosting this Ulk/Rab9-mediated alternative mitophagy may be a treatment strategy for preventing obesity-related cardiomyopathy.

Weakness, fatigue and trouble breathing are among the symptoms experienced by someone suffering heart failure with preserved ejection fraction (HFpEF). The pathology of the condition includes hypertrophy, fibrosis and stiffening of the heart with hyperphosphorylation of the cells’ sarcomeric proteins. Because this hyperphosphorylation is a key contributor to HFpEF pathology and because cardiosphere-derived stem cells (CDCs) show promise as a HFpEF treatment, Soetkamp and colleagues investigated whether CDC treatment reduces phosphorylation levels in the heart. Sure enough, administering CDCs to rats with HFpEF decreased the associated protein hyperphosphorylation compared with that seen in untreated animals. Bioinformatics analysis, based on the observed phosphorylation patterns and mass spectrometry data from test heart samples, suggested Protein Kinase C (PKC) as prime suspect behind the hyperphosphorylation—a suspicion strengthened by observing phosphorylation patterns in heart cells after inhibition or over-expression of PKC. The authors thus suggest CDCs alleviate HFpEF in part by reversing PKC-induced phosphoryation, and that PKC inhibition may be a desirable alternative treatment strategy especially as it avoids regulatory issues associated with cell-based therapies.

高血压是心脏肥大的主要原因——心脏肌肉质量增加。在短期内，这种增长有助于心脏应对压力超负荷，但如果压力持续存在，则会发生病理性肥大，包括肌肉纤维化和僵硬，并可能导致心力衰竭。有人提出，尽管常驻巨噬细胞促进组织修复，但浸润的巨噬细胞可能会使鳞片向病理学倾斜。为了更仔细地检查巨噬细胞在肥大中的作用，Revelo 及其同事使用精心设计的抗体治疗专门消耗了小鼠心脏驻留的巨噬细胞，使循环巨噬细胞不受影响。他们发现，虽然测试小鼠和对照小鼠在第一周对心脏压力超负荷的反应相似，但从长远来看，测试小鼠表现出心脏功能加速下降和更严重的纤维化。此外，循环巨噬细胞也耗尽的小鼠免受这种纤维化的影响。这表明招募的巨噬细胞确实抵消了常驻巨噬细胞的作用，从而促进了病理学。该团队表示，了解免疫细胞在心力衰竭中的作用最终将为未来的治疗提供信息。

患有肥胖症或糖尿病的人患心肌病的风险增加，最终可能导致心力衰竭。在细胞水平上与肥胖相关的心肌病的主要病理特征之一是线粒体功能下降，这可能是由典型线粒体自噬同时减少来解释的——这是一种功能失调的线粒体降解的过程。然而，最近发现了由 Ulk1 和 Rab9 因子介导的另一种线粒体自噬机制，现在 Tong 及其同事表明，这种替代形式实际上在 24 周内在长期高脂肪饮食的小鼠中稳定上调。相比之下，典型的线粒体自噬在大约两个月后停止。该团队表明，通过敲除 Ulk1 或 Rab9 功能丧失突变体的表达来抑制替代线粒体自噬进一步加剧了高脂肪饮食引起的心脏功能障碍，而 Rab9 在小鼠心脏中的过度表达增加了替代线粒体自噬并保护动物免于心脏功能障碍。总之，这些结果表明，在药理学上促进这种 Ulk/Rab9 介导的替代线粒体自噬可能是预防肥胖相关心肌病的一种治疗策略。

虚弱、疲劳和呼吸困难是患有射血分数保留的心力衰竭 (HFpEF) 的人所经历的症状之一。该病症的病理学包括肥大、纤维化和心脏硬化以及细胞肌节蛋白的过度磷酸化。由于这种过度磷酸化是 HFpEF 病理学的关键因素，并且因为心脏球源性干细胞 (CDC) 显示出作为 HFpEF 治疗的前景，Soetkamp 及其同事研究了 CDC 治疗是否会降低心脏中的磷酸化水平。果然，与未经治疗的动物相比，对患有 HFpEF 的大鼠施用 CDC 降低了相关的蛋白质过度磷酸化。生物信息学分析，基于观察到的磷酸化模式和来自测试心脏样本的质谱数据，建议蛋白激酶 C (PKC) 是过度磷酸化背后的主要嫌疑人——通过观察 PKC 抑制或过度表达后心脏细胞中的磷酸化模式加强了这种怀疑。作者因此建议 CDC 部分通过逆转 PKC 诱导的磷酸化来减轻 HFpEF，并且 PKC 抑制可能是一种理想的替代治疗策略，尤其是因为它避免了与基于细胞的疗法相关的监管问题。