DUSP9在2型糖尿病心肌病小鼠心肌损伤中的保护作用及其机制

doi:10.11958/20253111

天津医药 ›› 2026, Vol. 54 ›› Issue (3): 238-244.doi: 10.11958/20253111

DUSP9在2型糖尿病心肌病小鼠心肌损伤中的保护作用及其机制

张婧¹(), 魏玉英², 宁海虹³, 韦红梅¹, 王嘉玮³, 曹薇¹, 吴宾⁴^,^△()

1 新疆军区总医院营养科（邮编830000）
2 重症医学科
3 卫勤训练中心
4 核医学科

收稿日期:2025-10-13 修回日期:2025-11-11 出版日期:2026-03-15 发布日期:2026-03-17
通讯作者: △E-mail：xjwubin9210@163.com
作者简介:张婧（1982），女，副主任医师，主要从事营养与代谢性心血管疾病的基础与临床方面研究。E-mail：41133178@qq.com
基金资助:
新疆维吾尔自治区自然科学基金面上项目(2023D01C94)

Protective effect and mechanism of dual-specificity phosphatase 9 on myocardial injury in mice with type 2 diabetic cardiomyopathy

ZHANG Jing¹(), WEI Yuying², NING Haihong³, WEI Hongmei¹, WANG Jiawei³, CAO Wei¹, WU Bin⁴^,^△()

1 Department of Nutrition
2 Department of Critical Care Medicine
3 Health Service Training Center,
4 Department of Nuclear Medicine, General Hospital of Xinjiang Military Command, Urumqi 830000, China

Received:2025-10-13 Revised:2025-11-11 Published:2026-03-15 Online:2026-03-17
Contact: △E-mail：xjwubin9210@163.com

张婧, 魏玉英, 宁海虹, 韦红梅, 王嘉玮, 曹薇, 吴宾. DUSP9在2型糖尿病心肌病小鼠心肌损伤中的保护作用及其机制[J]. 天津医药, 2026, 54(3): 238-244.

ZHANG Jing, WEI Yuying, NING Haihong, WEI Hongmei, WANG Jiawei, CAO Wei, WU Bin. Protective effect and mechanism of dual-specificity phosphatase 9 on myocardial injury in mice with type 2 diabetic cardiomyopathy[J]. Tianjin Medical Journal, 2026, 54(3): 238-244.

摘要/Abstract

摘要：

目的探究双特异性磷酸酶9（DUSP9）对2型糖尿病心肌病（DCM）小鼠心肌损伤的保护作用及机制。方法采用高脂高糖饮食联合链脲酶素（STZ）腹腔注射建立2型糖尿病小鼠模型，建模成功后将小鼠随机分为对照（Control）组、糖尿病（DM）组、糖尿病+空病毒（DM+Vector）组、糖尿病+过表达DUSP9（DM+DUSP9）组。通过尾静脉注射腺相关病毒9型-DUSP9（AAV9-DUSP9）病毒或空病毒载体干预12周后，采用心脏超声评估心脏功能；检测各组的体质量、空腹血糖、心脏体质量比；取心脏组织进行苏木精-伊红染色、小麦胚芽凝集素（WGA）染色，观察心肌病理变化；酶联免疫吸附试验（ELISA）检测心肌组织炎性因子白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α水平；TUNEL法检测心肌细胞凋亡情况；Western blot检测细胞外信号调节激酶（ERK）、p38蛋白的磷酸化水平；透射电镜观察心肌组织中线粒体结构变化。结果与Control组相比，DM组和DM+Vector组小鼠心脏质量、心脏体质量比、心肌细胞横截面积，心肌组织IL-6、TNF-α水平，心肌细胞凋亡率，心肌组织p-ERK和p-p38表达增加，左室射血分数（LVEF）、左室短轴缩短率（LVFS）降低（P<0.05）。与DM+Vector组相比，DM+DUSP9组小鼠心脏质量、心脏体质量比，心肌细胞横截面积，心肌组织IL-6、TNF-α水平，心肌细胞凋亡率，心肌组织p-ERK和p-p38表达降低，LVEF、LVFS增加（P<0.05）。结论过表达DUSP9可改善DM小鼠心功能，其机制可能与DUSP9抑制ERK和p38磷酸化来减轻DCM小鼠的心肌炎症反应、细胞凋亡和线粒体损伤有关。

关键词: 糖尿病心肌病, 丝裂原激活蛋白激酶激酶类, 细胞凋亡, 线粒体, 双特异性磷酸酶类, 炎症

Abstract:

Objective To investigate the protective effect and underlying mechanism of dual-specificity phosphatase 9 (DUSP9) on myocardial injury in mice with type 2 diabetic cardiomyopathy (DCM). Methods A mouse model of type 2 diabetes was established using a high-fat, high-sugar diet combined with intraperitoneal injection of streptozotocin (STZ). After successful modeling, the mice were randomly divided into the control group (control), the diabetes mellitus (DM) group, the diabetes + empty vector (DM+Vector) group and the diabetes + DUSP9 overexpression (DM+DUSP9) group. Following a 12-week intervention via tail vein injection of AAV9-DUSP9 or empty viral vector, cardiac function was assessed by echocardiography. The body weight, fasting blood glucose and heart mass ratio were detected in mice of each group. Heart tissue samples were collected for histological examination using HE and WGA staining to observe myocardial pathological changes. The levels of inflammatory cytokines IL-6 and TNF-α in myocardial tissue were measured by ELISA. Myocardial cell apoptosis was detected by TUNEL assay. The phosphorylation levels of ERK and p38 proteins were evaluated by Western blot assay. Mitochondrial morphological changes were observed via transmission electron microscopy. Results Compared with the control group, significantly increased heart weight, heart-to-body weight ratio, cardiomyocyte cross-sectional area, levels of IL-6 and TNF-α in myocardial tissue, myocardial cell apoptosis rate and expressions of p-ERK and p-p38 in myocardial tissue were observed in the DM group and the DM+Vector group, and left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly decreased (P < 0.05). Compared with the DM+Vector group, the DM+DUSP9 group exhibited significantly decreased heart weight, heart-to-body weight ratio, cardiomyocyte cross-sectional area, levels of IL-6 and TNF-α, myocardial cell apoptosis rate and expressions of p-ERK and p-p38, while LVEF and LVFS were significantly increased (P < 0.05). Conclusion DUSP9 overexpression improves cardiac function in diabetic mice. The mechanism may be related to the inhibition of ERK and p38 phosphorylation by DUSP9, thereby alleviating myocardial inflammation, apoptosis and mitochondrial damage in diabetic cardiomyopathy mice.

Key words: diabetic cardiomyopathies, mitogen-activated protein kinase kinases, apoptosis, mitochondria, dual-specificity phosphatases, inflammation

中图分类号:

R542.2，R587.2

图/表 10

表1 各组小鼠一般生理参数比较（n=15，$\bar{x} \pm s$）

Tab.1 Comparison of general physiological parameters of mice between the four groups

组别	体质量/ g	空腹血糖/ （mmol/L）	心脏质量/mg	心脏体质量比/（mg/g）
Control组	30.70±0.73	6.48±0.72	119.05±5.18	4.04±0.35
DM组	24.21±2.66^a	25.96±2.58^a	151.79±8.14^a	5.68±0.29^a
DM+Vector组	23.10±1.94^a	26.24±3.24^a	149.55±7.81^a	5.85±0.42^a
DM+DUSP9组	27.35±1.63^a	24.57±1.60^a	137.03±6.34^ab	4.82±0.36^ab
F	53.480^＊＊	272.300^＊＊	69.620^＊＊	81.970^＊＊

图1 各组小鼠超声心动图图像

Fig.1 Echocardiographic images of mice in each group

表2 各组小鼠心功能指标比较（n=15，$\bar{x} \pm s$）

Tab.2 Comparison of cardiac function between the four groups of mice

组别	LVEDD/ mm	LVESD/ mm	LVEF/ %	LVFS/ %
Control组	3.55±0.15	2.50±0.13	75.05±4.11	38.18±3.02
DM组	4.55±0.10^a	3.39±0.09^a	55.43±2.04^a	22.46±2.16^a
DM+Vector组	4.43±0.21^a	3.50±0.14^a	53.77±3.07^a	23.49±3.07^a
DM+DUSP9组	4.08±0.12^ab	3.03±0.11^ab	60.78±2.01^ab	30.29±1.93^ab
F	132.600^＊＊	214.800^＊＊	162.500^＊＊	117.600^＊＊

图2 HE染色检测各组小鼠心肌组织病理变化（×400）

Fig.2 Histopathological changes in myocardial tissue of mice detected by HE staining (×400)

图3 WGA染色检测各组小鼠心肌横截面积（×400）

Fig.3 WGA staining of myocardial cross-sectional area in each group of mice (×400)

表3 各组小鼠心肌炎性因子水平比较（n=15，ng/L，$\bar{x} \pm s$）

Tab.3 Comparison of myocardial inflammatory factor levels between the four groups of mice

组别	IL-6	TNF-α
Control组	15.3±2.1	20.1±2.5
DM组	48.7±5.3^a	65.3±7.2^a
DM+Vector组	47.9±4.8^a	63.8±6.5^a
DM+DUSP9组	28.6±3.2^ab	35.4±4.1^ab
F	238.100^＊＊	251.400^＊＊

图4 各组小鼠心肌组织细胞凋亡情况（TUNEL染色，×400）绿色：TUNEL染色阳性；蓝色：DAPI染色阳性。

Fig.4 Apoptosis of myocardial tissue of mice (TUNEL staining, ×400)

图5 透射电镜观察各组小鼠心肌组织中线粒体损伤（×8 000）

Fig.5 Electron microscopy showing mitochondrial damage in myocardial tissue of mice in each group (×8 000)

图6 Western blot检测各组小鼠心肌组织ERK和p38蛋白表达水平

Fig.6 Western blot detection of ERK and p38 protein expression in myocardial tissue of mice in each group

表4 各组小鼠心肌组织p-ERK和p-p38蛋白表达水平比较（n=6，$\bar{x} \pm s$）

Tab.4 Comparison of levels of p-ERK and p-p38 expression in myocardial tissue of mice between the four groups of mice

组别	p-ERK/ERK	p-p38/p38
Control组	0.32±0.05	0.28±0.04
DM组	0.85±0.08^a	0.79±0.07^a
DM+Vector组	0.83±0.07^a	0.81±0.08^a
DM+DUSP9组	0.45±0.06^ab	0.39±0.05^ab
F	99.160^＊＊	115.600^＊＊

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DUSP9在2型糖尿病心肌病小鼠心肌损伤中的保护作用及其机制

Protective effect and mechanism of dual-specificity phosphatase 9 on myocardial injury in mice with type 2 diabetic cardiomyopathy

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