Insulin deficiency downregulated heat shock protein 60 and IGF-1 receptor signaling in diabetic myocardium.
Heat shock protein (Hsp)60 and IGF-1 receptor signaling protect cardiac muscle against injury. The abundance of cardiac IGF-1 receptor can be upregulated by Hsp60, but how diabetes modulates cardiac muscle Hsp60 has not yet been defined. We investigated the changes of Hsp60 and IGF-1 receptor signaling in the diabetic myocardium and studied how diabetes modulates Hsp60 and IGF-1 receptor in diabetic myocardium. In the streptozotocin (STZ)-induced diabetic rat, downregulation of Hsp60 and IGF-1 receptor occurred 4 days after induction of diabetes. IGF-1 activation of IGF-1 receptor, Mek, and Akt were reduced accordingly in the diabetic myocardium. The independent effect of insulin and hyperglycemia on Hsp60 was investigated in primary cardiomyocytes. Incubating cardiomyocytes with insulin was associated with dose-dependent increase of Hsp60 protein. In contrast, the abundance of Hsp60 was not affected by high concentration of glucose in these cells. To further determine the independent effects of hyperglycemia and insulin deficiency on the changes of myocardial Hsp60 and IGF-1 receptor, we used phlorizin to normalize blood glucose in diabetic rats. In the phlorizin-treated diabetic rats, myocardial Hsp60 was lower than that of the normal controls. In contrast, insulin treatment normalized myocardial Hsp60 in the diabetic rats. Because phlorizin does not alter insulin secretion, Hsp60 expression was modulated by insulin and not by hyperglycemia. Similar changes of Hsp60 and IGF-1 receptor were observed in the skeletal muscle of STZ-induced diabetic rats. These findings suggest that insulin deficiency is a novel mechanism that leads to downregulation of Hsp60 in diabetic muscle tissues. The development of diabetic cardiomyopathy might have involved downregulation of Hsp60 and subsequent reduction of IGF-1 receptor signaling.
Chen
Harn-Shen
HS
Department of Medicine, University of California, Med. Sci 1, C240, Irvine, CA 92697, USA.
Shan
Yue-Xin
YX
Yang
Tung-Lin
TL
Lin
Hong-Da
HD
Chen
Jaw-Wen
JW
Lin
Shing-Jong
SJ
Wang
Ping H
PH
D000818:Animals; D018834:Chaperonin 60 / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D015536:Down-Regulation; D005947:Glucose / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D007328:Insulin / Q000172:deficiency* / Q000378:metabolism; D000078790:Insulin Secretion; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction
D018834:Chaperonin 60; D007328:Insulin; D017526:Receptor, IGF Type 1; D005947:Glucose