EL-2：Hsp60 and Diabetic Cardiomyopathy

Ping H. Wang,  

Diabetic patients often have evidence of a cardiomyopathy that may occur without apparent microvascular or macrovascular diseases. Despite the anatomical and functional changes have been recognized for a long time, the molecular mechanisms involved in diabetic cardiomyopathy are not fully understood.  Recent data from our laboratory have shown a reduction in the amount of IGF-1 receptors and Hsp60 in the myocardium of animal models of diabetes. This contrasts to ischemic cardiomyopathy and hypertrophic cardiomyopathy, where there is an increased expression of IGF-1 receptors and Hsp60 in the myocardium.  Since IGF-1 has cardiac protective action, a reduction in IGF-1 receptor signaling could potentially lead to increased myocardial vulnerability during myocardial stress such as ischemia, and thus play a fundamental role for the development of diabetic cardiomyopathy. Interestingly, down-regulation of IGF-1 receptors in cardiac muscle was accompanied by concurrent reduction of Hsp60. Furthermore, ubiquitination of the IGF-1 receptor also increased in diabetic myocardium. Overexpression of Hsp60 inhibited apoptosis of cardiomyocytes in cardiomyocyte injuries, suggesting a protective effect of Hsp60. IGF-1 receptor signaling can be modulated by heat shock proteins.  Overexpressing Hsp60 in cardiomyocytes lead to up-regulation of IGF-1 receptor protein and augmentation of IGF-1 activated IGF-1 receptor tyrosine phosphorylation.  Down-regulation of Hsp60 with anti-sense oligonucleotides was associated with reduction of IGF-1 receptor protein and IGF-1 receptor signaling. The effect of Hsp60 on the IGF-1 receptor involves ubiquitination of the IGF-1 receptor. Overexpressing Hsp60 suppressed ubiquitination of the IGF-1 receptor and thereby augmented the abundance of IGF-1 receptors available for activation in the cardiac muscle.   Thus, the pro-survival action of Hsp60 may involve augmentation of IGF-1 receptor signaling. These findings render evidence that down-regulation of Hsp60 may be a fundamental mechanism contributing to impaired cardiac protective IGF-1 receptor signaling in the diabetic heart.