Effects of insulin replacement on cardiac apoptotic and survival pathways in streptozotocin-induced diabetic rats.
Increased myocyte apoptosis in diabetic hearts has been previously reported. Therefore, the purpose of this study was to evaluate the effects of insulin on cardiac apoptotic, hypertrophic, and survival pathways in streptozotocin (STZ)-induced diabetic rats. Forty-eight male Wistar rats at 8 weeks of age were randomly divided into control group (Control), STZ-induced (65 mg/kg STZ i.v.) Type 1-like diabetic rats (DM), and DM rats with 4 IU insulin replacement (DI) for 4 and 8 weeks, respectively. The levels of protein involved in cardiac apoptotic, hypertrophic, and survival pathways were measured by Western blotting. Cardiac mitochondrial-dependent apoptotic pathways, such as Bad, cytosolic cytochrome c, activated caspase 9 and 3, and calcineurin-nuclear factor activation transcription 3 (NFAT3) hypertrophic pathway in DM were increased compared to Control and attenuated in DI group after 8 weeks whereas those were not found after 4 weeks. Cardiac anti-apoptotic Bcl2 and phosphorylated-Bad were significantly decreased in DM group but not in DI group after 8 weeks. Insulin-like growth factor-I receptor (IGFIR), phosphatidylinositol 3'-kinase (PI3K), and the protein kinase B (Akt) were significantly decreased in DM relative to Control and DI after 8 weeks whereas those were not found after 4 weeks. Insulin replacement not only prevents activation of the cardiac mitochondrial-dependent apoptotic pathway and calcineurin-related NFAT3 hypertrophic pathway in diabetes but it also enhances the cardiac insulin/IGFIR-PI3K-Akt survival pathway, all of which are attenuated with insulin therapeutic duration-dependent manners. The findings may provide possible diabetes-related apoptotic, hypertrophic, and survival pathways for potentially preventing cardiac abnormality in diabetes.
Kuo
Wei-Wen
WW
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Chung
Li-Ching
LC
Liu
Cheng-Tzu
CT
Wu
Shih-Ping
SP
Kuo
Chia-Hua
CH
Tsai
Fuu-Jen
FJ
Tsai
Chang-Hai
CH
Lu
Min-Chi
MC
Huang
Chih-Yang
CY
Lee
Shin-Da
SD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013311:Streptozocin; D051025:bcl-Associated Death Protein / Q000378:metabolism
D007328:Insulin; D050778:NFATC Transcription Factors; D051025:bcl-Associated Death Protein; D013311:Streptozocin; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D053148:Caspase 3; D053453:Caspase 9