Zhang Yu, Zhang Liao, Li Pengjie, Qiu Lili, Qu Ying, Wu Yunhe, Song Haiyan
Department of Endocrinology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, PR China.
Department of Endocrinology, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, PR China.
Int Immunopharmacol. 2025 Jan 27;146:113860. doi: 10.1016/j.intimp.2024.113860. Epub 2024 Dec 18.
It is well-established that chronic hyperglycemia progressively destroys the heart structure, weakening function and leading to diabetic cardiomyopathy (DCM). Extracellular vesicles derived from adipose-derived stem cell (ADSC-EVs) have been reported to have anti-inflammatory and immune-modulating effects, but their role in DCM is still poorly understood. Therefore, this study investigated the impact of ADSC-EVs on DCM and potential mechanisms. ADSC-EVs were isolated from the conditioned media of ADSCs. DCM rat models were established using streptozotocin (STZ) in vivo, and high glucose (HG) stimulated H9c2 cardiomyocytes to establish in vitro model. Then mRNA sequencing identified Chit1 as a key gene. Both in vivo and in vitro experiments demonstrated that chitinase 1 (Chit1) and NLRP3/Caspase-1-mediated pyroptosis levels were significantly upregulated in myocardial tissue of rat diabetic cardiomyopathy and hyperglycemic cardiomyocytes, which was reversed by ADSC-EVs treatment. We next observed that in hyperglycemic cardiomyocytes, downregulating Chit1 also resulted in a decrease in NLRP3/Caspase-1-mediated pyroptosis proteins. To a certain extent, the inhibitory effect of ADSC-EVs on the NLRP3/Caspase-1 signaling pathway was reversed by Chit1 overexpression. Taken together, we identified a novel mechanism by which ADSC-EVs regulate NLRP3/Caspase-1-mediated pyroptosis through Chit1 to alleviate diabetic cardiomyopathy, offering an innovative strategy for DCM treatment.
众所周知，慢性高血糖会逐渐破坏心脏结构，削弱心脏功能并导致糖尿病性心肌病（DCM）。据报道，脂肪来源干细胞衍生的细胞外囊泡（ADSC-EVs）具有抗炎和免疫调节作用，但其在DCM中的作用仍知之甚少。因此，本研究调查了ADSC-EVs对DCM的影响及其潜在机制。ADSC-EVs从脂肪来源干细胞的条件培养基中分离得到。在体内使用链脲佐菌素（STZ）建立DCM大鼠模型，在体外使用高糖（HG）刺激H9c2心肌细胞建立模型。然后通过mRNA测序确定几丁质酶1（Chit1）为关键基因。体内和体外实验均表明，在大鼠糖尿病性心肌病的心肌组织和高血糖心肌细胞中，几丁质酶1（Chit1）和NLRP3/Caspase-1介导的细胞焦亡水平显著上调，而ADSC-EVs治疗可使其逆转。接下来我们观察到，在高血糖心肌细胞中，下调Chit1也会导致NLRP3/Caspase-1介导的细胞焦亡蛋白减少。在一定程度上，Chit1过表达可逆转ADSC-EVs对NLRP3/Caspase-1信号通路的抑制作用。综上所述，我们确定了一种新的机制，即ADSC-EVs通过Chit1调节NLRP3/Caspase-1介导的细胞焦亡以减轻糖尿病性心肌病，为DCM治疗提供了一种创新策略。
