Different influences of hyperglycemic duration on phosphorylated extracellular signal-regulated kinase 1/2 in rat heart.
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.
Naito
Zenya
Z
Department of Pathology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-0022, Japan. naito@nms.ac.jp
Takashi
En
E
Xu
Guang
G
Ishiwata
Toshiyuki
T
Teduka
Kiyoshi
K
Yokoyama
Munehiro
M
Yamada
Nokutaka
N
Sugisaki
Yuichi
Y
Asano
Goro
G
D000818:Animals; D003921:Diabetes Mellitus, Experimental; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D017127:Glycation End Products, Advanced; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases