Hypertension, which affects approximately a third of the global adult population, is a risk factor for stroke, myocardial infarction, and heart failure. Although blood pressure-lowering treatments are widely available, in approximately one third of patients, the condition remains uncontrolled. A thorough understanding of the complex pathophysiology of the condition would facilitate the search for much needed alternative treatments. To that end, Dikalova and colleagues have investigated Sirt3, an enzyme that tends to be at lower-than-usual levels in patients with hypertension and that regulates metabolic and antioxidant functions—both of which, if disturbed, can contribute to vascular dysfunction. The team showed that mice genetically engineered to overexpress Sirt3 had healthier blood vessels and lower blood pressure than control animals when subjected to experimentally induced hypertension. By contrast, Sirt3 depletion was shown to cause vascular inflammation and increased signs of vascular aging in mice. The team also confirmed the link between low Sirt3 levels and hypertension in humans. It is not clear why Sirt3 levels are low in certain people, but nevertheless, the findings suggest that boosting this enzyme may be a potential therapy for hypertension, say the authors.

The main energy source of the heart is fatty acid metabolism, but excessive lipids—resulting from diet-induced dyslipidemia, for example—can cause cardiomyocyte dysfunction. It’s known that lipid overload in the heart can cause increased activity of Drp1 (dynamin-related protein 1)—an enzyme that directs mitochondrial fission. But exactly how Drp1 becomes activated is unclear. In mice fed a high-fat diet, Hu and colleagues confirm that Drp1 activity and mitochondrial fission are abnormally increased, and that there are signs of heart dysfunction. They also show similar effects of a high-fat diet in monkeys. While levels of Drp1 mRNA were not altered in the mouse hearts, Drp1 protein acetylation was increased. The team went on to perform experiments on cultured rat cardiomyocytes, showing that incubation with the saturated fatty acid palmitate led to acetylation of Drp1 and thus its activation—resulting in excess mitochondrial fission and reduced cell viability. Mutation of Drp1 to prevent its acetlyation, by contrast, protected the cells. Together, the results reveal how dyslipidemia can contribute to heart cell dysfunction and suggest that Drp1 activity or acetylation state could be novel targets for treating obesity-related heart disease.

During an infection or injury, blood vessels become leaky to allow white blood cells to reach the sites of invasion or damage. But in sepsis, this normal inflammatory response becomes excessive and can lead to organ failure and death. The blood factor thrombin is a driver of vessel endothelium permeability, acting through its receptor, PAR1 (protease-activated receptor 1), on endothelial cells. But downstream molecular details of thrombin-induced endothelial permeability are lacking. Now, Li and colleagues show that a protein called BMX (bone marrow kinase on the X chromosome), which is highly expressed in endothelial cells and was known to interact with PAR1, actively suppresses thrombin-induced permeability. Studying mice with and without BMX after experimentally induced sepsis, the team showed that a lack of BMX exacerbated the condition, increasing vessel leakage. They also showed in cultured cells that BMX repressed thrombin-PAR1 signaling by phosphorylating and internalizing the receptor causing its deactivation. Indeed, PAR1 inhibition could reduce endothelial permeability in the sepsis-stricken, BMX-lacking mice and improve their survival. These results suggest that boosting BMX could be a treatment strategy for excessive or uncontrolled vascular leakage.

高血压约占全球成年人口的三分之一，是中风，心肌梗塞和心力衰竭的危险因素。尽管降低血压的治疗方法广泛可用，但在大约三分之一的患者中，这种情况仍未得到控制。对病情复杂的病理生理的透彻了解将有助于寻找急需的替代疗法。为此，迪卡洛娃（Dikalova）及其同事研究了Sirt3，一种在高血压患者中趋于低于正常水平的酶，它可以调节代谢和抗氧化功能-如果受到干扰，这两种酶都可能导致血管功能障碍。研究小组表明，经过基因工程改造以过度表达Sirt3的小鼠在遭受实验性高血压后，其血管更健康，血压更低。相比之下，Sirt3耗竭可导致小鼠血管发炎并增加血管衰老迹象。研究小组还证实了低Sirt3水平与人类高血压之间的联系。这组作者说，目前尚不清楚为什么某些人的Sirt3水平较低，但是，研究结果表明，增强该酶可能是治疗高血压的潜在疗法。

心脏的主要能量来源是脂肪酸代谢，但是过多的脂质（例如饮食引起的血脂异常）会导致心肌细胞功能障碍。众所周知，心脏中的脂质超负荷会导致Drp1（与动力蛋白有关的蛋白1）的活性增加，Drp1是一种指导线粒体裂变的酶。但是，究竟如何激活Drp1尚不清楚。Hu及其同事证实，在高脂饮食小鼠中，Drp1活性和线粒体裂变异常增加，并且有心脏功能障碍的迹象。它们还显示出高脂饮食对猴子的类似作用。虽然在小鼠心脏中Drp1 mRNA的水平没有改变，但Drp1蛋白的乙酰化却增加了。该小组继续对培养的大鼠心肌细胞进行实验，表明与饱和脂肪酸棕榈酸酯一起孵育会导致Drp1乙酰化，从而使其活化-导致线粒体过度分裂，并降低细胞活力。相比之下，Drp1的突变可防止其乙酸化，从而保护了细胞。总之，这些结果揭示了血脂异常如何导致心脏细胞功能障碍，并表明Drp1活性或乙酰化状态可能是治疗肥胖相关性心脏病的新靶标。

在感染或受伤期间，血管会渗漏，使白细胞到达侵袭或损坏的部位。但是在败血症中，这种正常的炎症反应变得过度，并可能导致器官衰竭和死亡。血液因子凝血酶是血管内皮通透性的驱动器，通过其受体PAR1（蛋白酶激活的受体1）作用于内皮细胞。但是缺乏凝血酶诱导的内皮通透性的下游分子细节。现在，Li及其同事证明了一种称为BMX（X染色体上的骨髓激酶）的蛋白在内皮细胞中高表达并已知与PAR1相互作用，可有效抑制凝血酶诱导的通透性。研究人员对实验性败血症后有无BMX的小鼠进行了研究，研究小组表明缺乏BMX会加剧这种情况，增加容器泄漏。他们还显示，在培养的细胞中，BMX通过磷酸化和内化受体使其失活来抑制凝血酶-PAR1信号传导。确实，PAR1抑制可降低败血症，缺乏BMX的小鼠的内皮通透性并提高其存活率。这些结果表明，加强BMX可能是过度或不受控制的血管渗漏的治疗策略。