Antiproliferative action of an angiotensin I-converting enzyme inhibitory peptide, Val-Tyr, via an L-type Ca2+ channel inhibition in cultured vascular smooth muscle cells.
Recent antihypertensive studies have demonstrated that small peptides with angiotensin I-converting enzyme (ACE) inhibitory activity had an ability to lower or to modulate a pressor blood pressure response in mild hypertensive subjects. However, the underlying mechanisms still remain unclear. Based on our previous finding that a small peptide, Val-Tyr (VY), was accumulated in the rat aorta and kidney as well as in the circulating blood system, we here investigated whether antihypertensive small peptides exert an antiproliferative effect on serum- or mitogen-induced human vascular smooth muscle cells (VSMCs). Treatment with some ACE inhibitory small peptides (VY, Ile-Trp [IW], and Ile-Val-Tyr [IVY]) had diverse effects on serum-stimulated VSMC proliferation that were independent of their ACE inhibitory activity, though only VY exerted a potent antiproliferative action. VY also showed a greater inhibition of WST-8 incorporation in response to angiotensin (Ang) II-stimulation than the other two small peptides. The attenuation of Ang II-stimulated WST-8 incorporation by VY was not affected by Ang II receptor antagonists (losartan and saralasin ([Sar1, Ile8]-Ang II)), indicating that the antiproliferative action of VY may not be due to the peptide's antagonistic effect against Ang II receptors. Treatment with VY had a significant inhibitory effect on the WST-8 incorporation induced by the stimulation of a voltage-gated L-type Ca2+ channel agonist, Bay K 8644. Even in the presence of a K+ channel blocker (paxillin) the inhibition was apparent, suggesting that VY inhibited the proliferation of VSMCs by serving as a natural L-type Ca2+ channel blocker, but not as a K+ channel agonist.
Toshiro
Matsui
M
Division of Bioscience and Bioenvironmental Sciences, Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan. tmatsui@agr.kyushu-u.ac.jp
Ueno
Takao
T
Tanaka
Mitsuru
M
Oka
Hiromi
H
Miyamotq
Takahisa
T
Osajima
Katsuhiro
K
Matsumoto
Kiyoshi
K
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000803:Angiotensin I / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D051419:Paxillin; D010750:Phosphoproteins / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003598:Cytoskeletal Proteins; D004151:Dipeptides; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D026902:Potassium Channel Blockers; D014662:Vasoconstrictor Agents; C414029:valyltyrosine; D000804:Angiotensin II; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000803:Angiotensin I