Insulin Deficiency Downregulated Heat Shock Protein 60 and IGF-1 Receptor Signaling in Diabetic Myocardium

Abstract

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. Diabetes 54: 175-181, 2005

Heat shock protein expression in diabetic nephropathy

“…Consistent with our results, a recent report has showed HSP60 upregulation in total protein extracts from diabetic rat kidneys (3,31). The distribution of HSP72 staining was suggestive of localization to both collecting ducts and thick ascending limbs, while HSP25 was overexpressed by the interstitial vessels, possibly in the pericytes surrounding the descending vasa recta, which are known to have a highly structured actin cytoskeleton (22).…”

Heat Shock Protein-60 and Risk for Cardiovascular Disease

“…Moreover, HSP60 and HSP10 overexpression in neonatal CMC amplified insulin-like growth factor-1 receptor (IGF-1R) activity through post-translational modifications [55]. In agreement with these data, diabetic myocardial lesions due to insulin deficiency were associated with reduction of HSP60 levels and, in turn, this reduction resulted in a decline of IGF-1R signalling functions [55,56]. The above reports represent the initial contributions to the relatively new field of molecular chaperones and chaperonopathies and metabolic diseases, which is bound to expand considerably in the near future.…”

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

“…In the heart, various studies have suggested a certain role for insulin-like growth factor (IGF-1) in the complex regulation of myocardial structure and function. In addition, IGF-1 was found to play a role in the delay of apoptosis and in the prolongation of survival of CM [3][4][5]. Hence, IGF-1 is a true candidate for cardioprotective therapy in diabetes mellitus.…”

“…Therefore, several studies have suggested that IGF-1 is involved in myocardial structure and function regulation. In addition to its effects on cell growth and differentiation, IGF-1 was reported to suppress or delay apoptosis of cardiomyocytes (CM) and prolong their survival [3][4][5]. Certain studies indicated that it can adjust apoptotic signaling cascades in the heart.…”