Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy.
The 12-lipoxygenase pathway is a key mediator of angiotensin II (Ang II)-induced effects in the adrenal cortex. We also recently demonstrated that Ang II increases 12- and 15-lipoxygenase product levels in vascular smooth muscle cells. However, the relation between lipoxygenase activation and Ang II-induced vascular smooth muscle cell hypertrophy is not known. We studied the effects of Ang II and 12-lipoxygenase products on both total cell protein content and the levels of the matrix protein fibronectin in quiescent porcine aortic smooth muscle cells. Ang II-induced increases in cellular protein content were attenuated by the specific 12-lipoxygenase inhibitor baicalein; in contrast, the cyclooxygenase inhibitor ibuprofen had no effect. Direct addition of the 12-lipoxygenase product 12-S-hydroxyeicosatetraenoic acid increased total cell protein content. We have recently shown that porcine vascular smooth muscle cell growth is potentiated in high glucose (25 mmol/L) culture conditions. We observed that both Ang II and 12-S-hydroxyeicosatetraenoic acid induced a greater increase in protein content in cells cultured for two passages in high glucose. Furthermore, Ang II and 12-S-hydroxyeicosatetraenoic acid also markedly increased fibronectin levels in cells cultured in high glucose. These results suggest that 12-lipoxygenase activation plays a key role in Ang II-induced vascular smooth muscle cell hypertrophy. Furthermore, both Ang II and lipoxygenase effects are enhanced in cells cultured under hyperglycemic conditions.
Natarajan
R
R
City of Hope Medical Center, Department of Diabetes and Endocrinology, Duarte, Calif.
Gonzales
N
N
Lanting
L
L
Nadler
J
J
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology* / Q000633:toxicity; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D006984:Hypertrophy; D007052:Ibuprofen / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D005353:Fibronectins; D044950:Flavanones; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D019808:Losartan; D007052:Ibuprofen