Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy.
Trimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated.



We established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes + trimetazidine (n = 6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.



Rats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes + trimetazidine group than the diabetic group (CVF, 4.75 ± 0.52 % vs. 11.04 ± 1.67 %, p < 0.05; PVCA/LA, 8.37 ± 0.51 vs. 17.97 ± 2.66, p < 0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes + trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis.



Early administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China.
Lei
L
Zhang
Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250012, People's Republic of China.
Wen-Yuan
WY
Ding
Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
Zhi-Hao
ZH
Wang
Department of Emergency, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
Meng-Xiong
MX
Tang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China.
Feng
F
Wang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China.
Ya
Y
Li
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China.
Ming
M
Zhong
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China.
Yun
Y
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, the State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People's Republic of China. zhangweisdu@gmail.com.|Department of Cardiology, Qilu Hospital of Shandong University, No.107 Wenhua West Road, Jinan, 250012, People's Republic of China. zhangweisdu@gmail.com.
Wei
W
Zhang
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D002404:Catheterization; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D003971:Diastole; D004195:Disease Models, Animal; D005355:Fibrosis; D018149:Glucose Intolerance / Q000097:blood / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014292:Trimetazidine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D001786:Blood Glucose; D007328:Insulin; D003094:Collagen; D000263:Adenylate Kinase; D014292:Trimetazidine
Apoptosis; Autophagy; Diabetic cardiomyopathy; Myocardial fibrosis; Trimetazidine