Abstract
Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/1 glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/1 glucose showed statistically significant increases in protein kinase C activities, the expression of PKCβII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/1 glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.
| Original language | English |
|---|---|
| Pages (from-to) | 480-487 |
| Number of pages | 8 |
| Journal | Diabetologia |
| Volume | 44 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2001 |
| Externally published | Yes |
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Keywords
- Aldose reductase inhibitor
- Diabetic macroangiopathy
- Oxidative stress
- Platelet-derived growth factor
- Protein kinase C
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity. / Nakamura, J.; Kasuya, Y.; Hamada, Y.; Nakashima, E.; Naruse, Keiji; Yasuda, Y.; Kato, K.; Hotta, N.
In: Diabetologia, Vol. 44, No. 4, 2001, p. 480-487.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity
AU - Nakamura, J.
AU - Kasuya, Y.
AU - Hamada, Y.
AU - Nakashima, E.
AU - Naruse, Keiji
AU - Yasuda, Y.
AU - Kato, K.
AU - Hotta, N.
PY - 2001
Y1 - 2001
N2 - Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/1 glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/1 glucose showed statistically significant increases in protein kinase C activities, the expression of PKCβII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/1 glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.
AB - Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/1 glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/1 glucose showed statistically significant increases in protein kinase C activities, the expression of PKCβII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/1 glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.
KW - Aldose reductase inhibitor
KW - Diabetic macroangiopathy
KW - Oxidative stress
KW - Platelet-derived growth factor
KW - Protein kinase C
UR - http://www.scopus.com/inward/record.url?scp=0035062863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035062863&partnerID=8YFLogxK
U2 - 10.1007/s001250051646
DO - 10.1007/s001250051646
M3 - Article
C2 - 11357479
AN - SCOPUS:0035062863
VL - 44
SP - 480
EP - 487
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 4
ER -