胆碱能药物通过调节肠道细菌成分脂多糖诱导的 ERK/Egr-1 通路减少代谢性炎症和糖尿病心肌损伤,The FASEB Journal

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胆碱能药物通过调节肠道细菌成分脂多糖诱导的 ERK/Egr-1 通路减少代谢性炎症和糖尿病心肌损伤
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-04-11 , DOI: 10.1096/fj.202202108r
Qing Wu ₁ , Ming Zhao ₁ , Dongling Li ₁ , Xi He ₁ , Weijin Zang ₁

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自主神经失衡和代谢性炎症是糖尿病心肌病的重要病理过程。肠道菌群失调和细菌成分脂多糖 (LPS) 水平升高与糖尿病心肌损伤有关，但肠道微生物影响代谢性炎症和心脏损伤的机制仍不清楚。我们确定了抑制胆碱酯酶以改善迷走神经活性的吡啶斯的明 (PYR) 是否可以调节紊乱的肠道微生物群并减轻肠道屏障功能障碍、代谢性内毒素血症和糖尿病炎症。Db/db 小鼠表现出高血糖水平、胰岛素抵抗、低迷走神经活动和糖尿病心肌损伤。Db/db 小鼠还表现出肠道微生物群扰动和随后的肠道屏障功能破坏，导致 LPS 大量涌入，代谢性内毒素血症和炎症。PYR 改善了 db/db 小鼠失调的葡萄糖和脂质代谢，调节了肠道微生物群的整体结构，选择性地增加了抗炎细菌的丰度，并减少了促炎和潜在致病细菌的丰度。重要的是，PYR 增强了迷走神经活性，恢复了肠道菌群稳态，并减轻了肠道屏障功能障碍。因此，LPS 诱导的细胞外信号调节激酶 (ERK)/早期生长反应-1 (Egr-1) 通路和随之而来的代谢性炎症受到抑制，最终，db 中的心脏肥大、纤维化、氧化应激和功能障碍得到改善/db 老鼠。通过将原代新生大鼠心室心肌细胞暴露于高葡萄糖 (HG) 和 LPS 来诱导体外心肌细胞损伤。体外分析表明，HG + LPS 可诱导 ERK1/2 磷酸化、Egr-1 表达、炎症和细胞凋亡，这些可被乙酰胆碱 (ACh) 抑制。Alpha 7 烟碱 ACh 受体而非毒蕈碱 2 ACh 受体在 ACh 介导的抗炎作用和抑制 HG + LPS 给药的新生大鼠心室心肌细胞中的 ERK/Egr-1 通路中起重要作用。PYR 和 ACh 通过抑制 LPS 诱导的 ERK/Egr-1 通路和代谢炎症来改善糖尿病心肌损伤。迷走神经-肠道-心脏轴为糖尿病的复杂机制提供了新的见解，并提供了新的治疗靶点。Alpha 7 烟碱 ACh 受体而非毒蕈碱 2 ACh 受体在 ACh 介导的抗炎作用和抑制 HG + LPS 给药的新生大鼠心室心肌细胞中的 ERK/Egr-1 通路中起重要作用。PYR 和 ACh 通过抑制 LPS 诱导的 ERK/Egr-1 通路和代谢炎症来改善糖尿病心肌损伤。迷走神经-肠道-心脏轴为糖尿病的复杂机制提供了新的见解，并提供了新的治疗靶点。Alpha 7 烟碱 ACh 受体而非毒蕈碱 2 ACh 受体在 ACh 介导的抗炎作用和抑制 HG + LPS 给药的新生大鼠心室心肌细胞中的 ERK/Egr-1 通路中起重要作用。PYR 和 ACh 通过抑制 LPS 诱导的 ERK/Egr-1 通路和代谢炎症来改善糖尿病心肌损伤。迷走神经-肠道-心脏轴为糖尿病的复杂机制提供了新的见解，并提供了新的治疗靶点。

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Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide-induced ERK/Egr-1 pathway

Autonomic imbalance and metabolic inflammation are important pathological processes in diabetic cardiomyopathy. Gut microbiota dysbiosis and increased levels of bacterial component lipopolysaccharide (LPS) are associated with diabetic myocardial injury, but the mechanism by which gut microbes affect metabolic inflammation and cardiac injury remains unclear. We determined whether pyridostigmine (PYR), which inhibits cholinesterase to improve vagal activity, could regulate the disordered gut microbiota and attenuate gut barrier dysfunction, metabolic endotoxemia, and inflammation in diabetes. Db/db mice exhibited high blood glucose levels, insulin resistance, low vagal activity, and diabetic myocardial injury. Db/db mice also exhibited gut microbiota perturbations and subsequent disruption of gut barrier function, resulting in an influx of LPS, metabolic endotoxemia, and inflammation. PYR ameliorated the dysregulated glucose and lipid metabolism, modulated the overall structure of the gut microbiota, selectively enhanced the abundance of anti-inflammatory bacteria, and reduced the abundance of proinflammatory and potentially pathogenic bacteria in db/db mice. Importantly, PYR enhanced vagal activity, restored gut microbiota homeostasis, and alleviated gut barrier dysfunction. Therefore, the LPS-induced extracellular signal-regulated kinase (ERK)/early growth response-1 (Egr-1) pathway and consequent metabolic inflammation were inhibited, and eventually, cardiac hypertrophy, fibrosis, oxidative stress, and dysfunction were ameliorated in db/db mice. In vitro cardiomyocyte injury was induced by exposing primary neonatal rat ventricular cardiomyocytes to high glucose (HG) and LPS. In vitro analyses showed that HG + LPS induced ERK1/2 phosphorylation, Egr-1 expression, inflammation, and cell apoptosis, which were inhibited by acetylcholine (ACh). Alpha 7 nicotinic ACh receptor but not muscarinic 2 ACh receptor plays an important role in ACh-mediated anti-inflammatory effects and inhibiting the ERK/Egr-1 pathway in HG + LPS-administered neonatal rat ventricular cardiomyocytes. PYR and ACh ameliorated diabetic myocardial injury by inhibiting the LPS-induced ERK/Egr-1 pathway and metabolic inflammation. The vagus–gut–heart axis has provided new insights into the complex mechanisms of diabetes and offers novel therapeutic targets.

更新日期：2023-04-11

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