Inhibition of JNK by novel curcumin analog C66 prevents diabetic cardiomyopathy with a preservation of cardiac metallothionein expression.
The development of diabetic cardiomyopathy is attributed to diabetic oxidative stress, which may be related to the mitogen-activated protein kinase (MAPK) c-Jun NH2-terminal kinase (JNK) activation. The present study tested a hypothesis whether the curcumin analog C66 [(2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene) cyclohexanone] as a potent antioxidant can protect diabetes-induced cardiac functional and pathogenic changes via inhibition of JNK function. Diabetes was induced with a single intraperitoneal injection of streptozotocin in male C57BL/6 mice. Diabetic and age-matched control mice were randomly divided into three groups, each group treated with C66, JNK inhibitor (JNKi, SP600125), or vehicle (1% CMC-Na solution) by gavage at 5 mg/kg every other day for 3 mo. Neither C66 nor JNKi impacted diabetic hyperglycemia and inhibition of body-weight gain, but both significantly prevented diabetes-induced JNK phosphorylation in the heart. Compared with basal line, cardiac function was significantly decreased in diabetic mice at 3 mo of diabetes but not in C66- or JNKi-treated diabetic mice. Cardiac fibrosis, oxidative damage, endoplasmic reticulum stress, and cell apoptosis, examined by Sirius red staining, Western blot, and thiobarbituric acid assay, were also significantly increased in diabetic mice, all which were prevented by C66 or JNKi treatment under diabetic conditions. Cardiac metallothionein expression was significantly decreased in diabetic mice but was almost normal in C66- or JNKi-treated diabetic mice. These results suggest that, like JNKi, C66 is able to prevent diabetic upregulation of JNK function, resulting in a prevention of diabetes-induced cardiac fibrosis, oxidative stress, endoplasmic reticulum stress, and cell death, along with a preservation of cardiac metallothionein expression.
The First Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky;
Yonggang
Y
Wang
The First Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky;
Shanshan
S
Zhou
The First Hospital of Jilin University, Changchun, China;
Wanqing
W
Sun
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky;
Kristen
K
McClung
The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China; Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
Yong
Y
Pan
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
Guang
G
Liang
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China; Departments of Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; and.
Yi
Y
Tan
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
Yunjie
Y
Zhao
The First Hospital of Jilin University, Changchun, China;
Quan
Q
Liu
The First Hospital of Jilin University, Changchun, China;
Jian
J
Sun
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou, China; Departments of Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; and l0cai001@louisville.edu.
Lu
L
Cai
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004396:Coloring Agents; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D004452:Echocardiography; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005355:Fibrosis / Q000473:pathology; D006321:Heart / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
C575443:2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone; D001597:Benzylidene Compounds; D004396:Coloring Agents; D003512:Cyclohexanones; D047428:Protein Kinase Inhibitors; D008668:Metallothionein; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin
JNK; cardiac; diabetes; metallothionein; oxidative stress