Extracellular signal-regulated kinase (ERK) 1/2 is an important intracellular
proteinase associated with myocardial protection against
heart injury.
Hyperglycemia was also reported to be highly involved in
heart injury by the formation of
advanced glycation end products (AGEs) in myocardial
protein, resulting in its altered structure and function. However, the effect of this glycation on
mitogen-activated protein kinases, particularly ERK1/2, in the myocardium is largely unclarified. In this study, we investigated whether the glycation of an intracellular
protein, ERK1/2, would result in ERK1/2-AGEs formation that adversely affects ERK1/2 activation in the rat heart under
hyperglycemia.
Hyperglycemia was induced by injection of
streptozotocin (STZ) and hearts were examined 4 and 20 weeks after STZ treatment. By immunohistochemical staining and Western blotting, it was determined that the level of phosphorylated ERK1/2 in the rat heart under
hyperglycemia 20 weeks after STZ treatment decreased markedly by about 50% of that of the time-matched control group, whereas in the case of 4 weeks after STZ treatment, it increased by about 2.7-fold that of the time-matched group. The level of deposition of AGEs in
proteins of the myocardium increased significantly depending on the duration of
hyperglycemia. Twenty weeks after STZ treatment, two clear bands corresponding to 44- and 42-kDa AGEs were detected by Western blotting: these corresponded to
protein sizes of ERK1/2. The immunoprecipitation method further confirmed the formation and the increased intensity of ERK1/2-AGEs in the rat heart under
hyperglycemia for 20 weeks. These results demonstrate that long-term
hyperglycemia may inhibit ERK1/2 phosphorylation in the myocardium, whereas a short-term (4 weeks)
hyperglycemia enhances its phosphorylation. The ERK1/2 phosphorylation under long-term
hyperglycemia is very different from that under short-term
hyperglycemia. In addition, this inhibition of ERK1/2 activation appears to be dependent on the formation of ERK1/2-AGEs under long-term
hyperglycemia, which may be related in part to the etiology of
diabetic cardiomyopathy. It also suggests that the formation of AGEs in intracellular
enzymes and
proteins under
hyperglycemia could play important roles in the development of
diabetes complications.