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

doi:10.11958/20253111

Abstract

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

CLC Number:

R542.2，R587.2

Figures/Tables 10

References 20

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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^＊＊

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^＊＊

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^＊＊

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^＊＊

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^＊＊