Formation of an F2-isoprostane in vascular smooth muscle cells by elevated glucose and growth factors.
Recently a series of non-cyclooxygenase-derived prostanoids were identified in vivo in humans and in animal models of free radical injury as products of free radical-catalyzed peroxidation of arachidonic acid. One of these, an F2-isoprostane, 8-epiprostaglandin F2 alpha (8-epi-PGF 2 alpha), is a potent renal vasoconstrictor and can increase vascular smooth muscle cell (VSMC) DNA synthesis. In the present study we have evaluated whether F2-isoprostanes play a role in diabetic vascular dysfunction by studying the formation of 8-epi-PGF2 alpha in porcine VSMC (PVSMC) cultured under hyperglycemic conditions. 8-Epi-PGF2 alpha levels were quantitated by a specific enzyme immunoassay. We also examined whether certain VSMC growth factors, such as angiotensin II, platelet-derived growth factor, and transforming growth factor-beta, could also regulate the formation of 8-epi-PGF2 alpha. We observed that PVSMC cultured under high glucose (HG) conditions produced significantly higher amounts of 8-epi-PGF2 alpha compared with normal glucose (NG) conditions (3.7 +/- 0.13 ng/10(6) cells in HG vs. 2.9 +/- 0.2 ng/10(6) cells in NG, P < 0.05). Furthermore, all three growth factors tested evoked significant dose-dependent formation of 8-epi-PGF2 alpha (ranging from 125 to 220% of control). These results suggest that 8-epi-PGF2 alpha formation, as a result of hyperglycemia or due to growth factor action, may lead to increased VSMC growth and contribute to the complications of diabetes and cardiovascular disease.
Natarajan
R
R
Department of Diabetes, Endocrinology, and Metabolism, City of Hope Medical Center, Duarte, California 91010, USA.
Lanting
L
L
Gonzales
N
N
Nadler
J
J
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015237:Dinoprost / Q000819:agonists / Q000031:analogs & derivatives* / Q000096:biosynthesis; D028441:F2-Isoprostanes; D005947:Glucose / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000975:Antioxidants; D028441:F2-Isoprostanes; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011759:Pyrrolidines; D013859:Thiocarbamates; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C020972:pyrrolidine dithiocarbamic acid; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D010741:Phospholipases A; D011796:Quinacrine; D005947:Glucose