Inhibition of dynamin-related protein 1 protects against myocardial ischemia-reperfusion injury in diabetic mice.
Many cardioprotective pharmacological agents failed to exert their protective effects in diabetic hearts subjected to myocardial ischemia/reperfusion (MI/R). Identify the molecular basis linking diabetes with MI/R injury is scientifically important and may provide effective therapeutic approaches. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in MI/R injury under non-diabetic conditions. Importantly, recent studies indicated that Drp1-mediated mitochondrial fission is enhanced in the myocardium of diabetic mice. The above evidences suggested that Drp1 may be one critical molecule linking diabetes with MI/R injury. We hypothesized that inhibition of Drp1 may be effective to reduce MI/R injury in diabetic hearts.



High-fat diet and streptozotocin-induced diabetic mice were subjected to MI/R or sham operation. Mdivi-1 (1.2 mg/kg), a small molecule inhibitor of Drp1 or vehicle was administrated 15 min before the onset of reperfusion. Outcome measures included mitochondrial morphology, mitochondrial function, myocardial injury, cardiac function and oxidative stress.



Mitochondrial fission was significantly increased following MI/R as evidenced by enhanced translocation of Drp1 to mitochondria and decreased mitochondrial size. Delivery of Mdivi-1 into diabetic mice markedly inhibited Drp1 translocation to the mitochondria and reduced mitochondrial fission following MI/R. Inhibition of Drp1 in diabetic hearts improved mitochondrial function and cardiac function following MI/R. Moreover, inhibition of Drp1 reduced myocardial infarct size and serum cardiac troponin I and lactate dehydrogenase activities. These cardioprotective effects were associated with decreased cardiomyocyte apoptosis and malondialdehyde production and increased activities of antioxidant enzyme manganese superoxide dismutase.



Pharmacological inhibition of Drp1 prevents mitochondrial fission and reduces MI/R injury in diabetic mice. The findings suggest Drp1 may be a potential novel therapeutic target for diabetic cardiac complications.
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710003, China.|Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China.
Mingge
M
Ding
Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
Qianqian
Q
Dong
Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032, China.
Zhenghua
Z
Liu
Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032, China.
Zheng
Z
Liu
Department of Geriatrics, Xi'an Central Hospital, Xi'an, 710003, China.
Yinxian
Y
Qu
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China.
Xing
X
Li
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China.
Cong
C
Huo
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China.
Xin
X
Jia
Department of Physiology, Fourth Military Medical University, 169 Changlexi Road, Xi'an, 710032, China. fufeng048@126.com.
Feng
F
Fu
Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi'an, 710032, China. xmwang@fmmu.edu.cn.
Xiaoming
X
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D052999:Quinazolinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000378:metabolism; D019210:Troponin I / Q000097:blood
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D002317:Cardiovascular Agents; D052999:Quinazolinones; D019210:Troponin I; D008315:Malondialdehyde; D013311:Streptozocin; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; C486391:Dnm1l protein, mouse; D034281:Dynamins
Diabetes; Drp1; Ischemia–reperfusion; Mitochondrial fission