Angiotensin II induces TIMP-1 production in rat heart endothelial cells.
Angiotensin II (AII) was found to upregulate tissue inhibitor of metalloproteineses-1 (TIMP-1) gene expression in rat heart endothelial cells in a dose and time-dependent manner. The maximal stimulation of TIMP-1 mRNA was achieved by 2 h after the addition of AII. This effect was blocked by losartan, an AT1 receptor antagonist and by calphostin C, a protein kinase C inhibitor. Addition of cycloheximide superinduced and actinomycin D abolished the induction. These results suggest that AII stimulates TIMP-1 production by a protein kinase C dependent pathway which is dependent upon de novo RNA synthesis. Immunoprecipitation experiment showed an enhanced band of 28 kDa from the conditioned medium of AII-treated cultures. Immunoblot analysis revealed that TIMP-1 was detectable in the conditioned medium 4 h after AII stimulation. Since endothelial cells line the blood vessels and sense the rise in AII associated with hypertension, the TIMP-1 released by these cells may provide an initial trigger leading to cardiac fibrosis in angiotensin-renin dependent hypertension.
Chua
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CC
Division of Geriatric Medicine, East Tennessee State University, Johnson City 37614-0429, USA.
Hamdy
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RC
Chua
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BH
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004727:Endothelium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D009206:Myocardium / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007093:Imidazoles; D011480:Protease Inhibitors; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D019714:Tissue Inhibitor of Metalloproteinases; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D011493:Protein Kinase C; D019808:Losartan