Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University.
Department of Immunology, Allergy, and Vascular Biology, Graduate School of Medical Sciences, Kumamoto University.
Circ J. 2018 Jan 25;82(2):437-447. doi: 10.1253/circj.CJ-17-0327. Epub 2017 Sep 8.
Recently, it was reported that angiopoietin-like protein 2 (ANGPTL2) secreted from a pathologically stressed heart accelerates cardiac dysfunction in an autocrine/paracrine manner, and that suppression of ANGPTL2 production in the heart restored cardiac function and myocardial energy metabolism, thereby blocking heart failure (HF) development. Interestingly, circulating ANGPTL2 concentrations reportedly increase in HF patients, suggesting a possible endocrine effect on cardiac dysfunction. However, it remains unclear why circulating ANGPTL2 increases in those subjects and whether circulating ANGPTL2 alters cardiac function in an endocrine manner.Methods and Results:It was found that circulating ANGPTL2 levels are positively correlated with left atrial diameter and pulmonary capillary wedge pressure, and are inversely proportional to the percent of ejection fraction in patients with dilated cardiomyopathy. Furthermore, in mice, circulating ANGPTL2 concentrations increased as HF developed following transverse aorta constriction (TAC), and were inversely correlated with the percent of fractional shortening. Interestingly, although circulating ANGPTL2 concentrations significantly increased in transgenic mice overexpressing keratinocyte-derived ANGPTL2, no pathological cardiac remodeling was seen. Furthermore, it was observed that there was no difference in HF development between transgenic mice and controls following TAC surgery.
Circulating ANGPTL2 levels increase in subjects experiencing cardiac dysfunction. However, circulating ANGPTL2 does not promote cardiac dysfunction in an endocrine manner, and increased levels of circulating ANGPTL2 seen during HF are a secondary effect of increased ANGPTL2 secretion from stressed hearts in HF pathologies.
最近有报道称，病理性应激心脏分泌的血管生成素样蛋白 2（ANGPTL2）以自分泌/旁分泌的方式加速心脏功能障碍，而心脏中 ANGPTL2 产生的抑制恢复了心脏功能和心肌能量代谢，从而阻断心力衰竭（HF）的发展。有趣的是，HF 患者的循环 ANGPTL2 浓度升高，提示其对心脏功能障碍可能存在内分泌作用。然而，循环 ANGPTL2 在这些患者中升高的原因以及循环 ANGPTL2 是否以内分泌方式改变心脏功能仍不清楚。
研究发现，扩张型心肌病患者的循环 ANGPTL2 水平与左心房直径和肺毛细血管楔压呈正相关，与射血分数的百分比呈负相关。此外，在小鼠中，随着横主动脉缩窄（TAC）后 HF 的发展，循环 ANGPTL2 浓度增加，与分数缩短的百分比呈负相关。有趣的是，尽管过表达角蛋白细胞衍生的 ANGPTL2 的转基因小鼠中循环 ANGPTL2 浓度显著升高，但并未观察到病理性心脏重塑。此外，还观察到 TAC 手术后转基因小鼠与对照组在 HF 发展方面没有差异。
心脏功能障碍患者的循环 ANGPTL2 水平升高。然而，循环 ANGPTL2 不以内分泌方式促进心脏功能障碍，HF 期间循环 ANGPTL2 水平升高是 HF 病理中应激心脏中 ANGPTL2 分泌增加的继发效应。
