武汉云克隆科技股份有限公司

Abstract

Biglycan is a small leucine rich proteoglycan and is important for the structural integrity of the extracellular matrix, but also serves as a danger signal and triggers sterile inflammation. Whether biglycan is beneficial or delirious in angiotensin induced heart failure, a model were remodeling as well as inflammation plays a crucial role, is unkown. The present study investigated whether gene deletion of biglycan influences cardiac inflammatory stress response, adverse remodeling as well as apoptosis leading to cardiac dysfunction and mortality after 3 weeks of angiotensin induced heart failure in vivo.

Methods and results: Biglycan knockout mice (BGN-/-) and their controls (WT) were subjected to receive angiotensin II (ANGII) or saline for 3 weeks via osmotic mini pump and 21 days later LV function was analyzed invasively. ANGII induced significant cardiac inflammation (increased CD3 (+3.5 fold) and CD11b+ (+5 fold) cells) as well as cardiac dysfunction in WT-ANGII animals. Interestingly, deletion of BGN impaired cardiac function (significantly impaired stroke work, cardiac output and diastolic function) when BGN-/- ANGII were compared to WT-ANGII. This was associated with increased inflammation (CD3, CD11, cytokine expression TNF-alpha) as well as increased collagen accumulation as detrimental LV remolding in BGN-/- ANGII compared to WT-ANGII. This all increased mortality in BGN-/- ANGII (45% vs 0%) in ANGII induced heart failure. Interestingly, we documented an increased number of myofibroblasts in BGN-/- ANGII, which might explain the accumulation of matrix as well as increased inflammatory response compared to WT-ANGII

Conclusions: Loss of biglycan increased the inflammatory response, which impaired cardiac remodeling and function during ANGII induced heart failure leading to high mortality in vivo. Therefore, biglycan in ANGII induced heart failure seems to be beneficial by preserving the structural integrity of the matrix and preventing increased transdifferentiation of fibroblasts to myofibroblasts.

摘要

Biglycan是一个小的亮氨酸富集蛋白多糖，它对细胞外基质的结构完整性很重要，但同时也是一种危险信号，能触发无菌性炎症。我们重构了一个模型，在血管紧张素诱发的心力衰竭中，biglycan是否是有益的或错乱的，炎症是否起着至关重要的作用，这些是不清楚的。当前的研究证明了在体内3周的血管紧张素诱发心脏衰竭后，biglycan基因的缺失是否会影响心脏炎症应激应答、不良重构以及细胞凋亡，从而导致心脏功能障碍和死亡。

方法和结果：Biglycan基因敲除小鼠（BGN-/-）及其对照（WT）通过渗透式微型泵摄入血管紧张素II（ANGII）或生理盐水3周，21天后对LV的功能进行了分析。在WT-ANGII动物中，血管紧张素II引起严重的心脏炎症（CD3（+3.5倍）和CD11b+（+5倍）细胞增加）以及心脏功能障碍。有趣的是，当BGN-/- ANGII组和WT-ANGII组对比时，BGN的缺失损害了心脏功能（严重受损的搏出功、心脏输出和舒张功能）。这与增加的炎症（CD3、CD11、细胞因子表达TNF-alpha）以及增加的胶原蛋白积累有关，与WT-ANGII组相比，BGN-/- ANGII组中LV的重构是有害的。在血管紧张素II引起的心力衰竭中，这些因素增加了BGN-/-ANGII组模型动物的的死亡率（45%对0%）。有趣的是，我们发现在BGN-/-ANGII组中，肌纤维母细胞数量增加了，这可能解释了与WT-ANGII组相比，BGN-/-ANGII组基质的积累以及炎症反应的增加。

结论：在血管紧张素II诱导心力衰竭而导致机体高死亡率的过程中，Biglycan的缺失增加了炎症反应，这损害了心脏的重构和功能。因此，在血管紧张素II诱发的心力衰竭中，biglycan似乎是有益的，它保留了基质的结构完整性，阻碍了纤维母细胞分化成肌成纤维细胞。