Abstract
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.
Similar content being viewed by others
Article PDF
References
Dzau VJ : Tissue angiotensin and pathobiology of vascular disease. Hypertension 2001; 37: 1047–1052.
Ortega MR, Lorenzo O, Ruperez M, et al: Role of the renin-angiotensin system in vascular diseases. Hypertension 2001; 38; 1382–1387.
Somlyo AP, Somlyo AV : Signal transduction and regulation in smooth muscle. Nature 1994; 372: 231–236.
Miura S, Jhang J, Matsuo Y, Saku K, Karnik SS : Activation of extracellular signal-activated kinase by angiotensin II-induced Gq-independent epidermal growth factor receptor transactivation. Hypertens Res 2004; 27: 765–770.
Chai SY, Perich R, Jackson B, Mendelsohn FAO, Johnston CI : Acute and chromic effects of angiotensin-converting enzyme inhibitors on tissue angiotensin-converting enzyme. Clin Exp Pharm Physiol 1992; 19 ( Suppl 19): S7–S12.
Nong Z, Stassen JM, Moons L, Collen D, Janssens S : Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Circulation 1996; 94: 1941–1947.
Bravo R, Somoza B, Gayo MR, Gonzalez C, Ruilope LM, Alfonso ZMSF : Differential effect of chronic antihypertensive treatment on vascular smooth muscle cell phenotype in spontaneously hypertensive rats. Hypertension 2001; 37: e4–e10.
Criscione L, Bradley WA, Buhlmayer P, et al: Valsartan: preclinical and clinical profile of an antihypertensive angiotensin II antagonist. Cardiovasc Drug Rev 1995; 13: 230–250.
Striessnig J, Grabner M, Mitterdorfer J, Hering S, Sinnegger MJ, Glossmann H : Structural basis of drug binding to L Ca2+ channels. Trends Pharmacol Sci 1998; 19: 108–115.
Miura S, Saku K, Karnik SS : Molecular analysis of the structure and function of the angiotensin II type 1 receptor. Hypertens Res 2003; 26: 937–943.
Karlberg BE : Cough and inhibition of the renin-angiotensin system. J Hypertens 1993; 11 ( Suppl 3): S49–S52.
Matsufuji H, Matsui T, Seki E, Osajima K, Nakashima M, Osajima Y : Angiotensin I-converting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle. Biosci Biotechnol Biochem 1994; 58: 2244–2245.
Matsui T, Yukiyoshi A, Doi S, Sugimoto H, Yamada H, Matsumoto K : Gastrointestinal enzyme production of bioactive peptides from royal jelly protein and their antihypertensive ability in SHR. J Nutr Biochem 2002; 13: 80–86.
Matsui T, Li CH, Tanaka T, Maki T, Osajima Y, Matsumoto K : Depressor effect of wheat germ hydrolysate and its novel angiotensin I-converting enzyme inhibitory peptide, Ile-Val-Tyr, and the metabolism in rats and human plasma. Biol Pharm Bull 2000; 23: 427–431.
Kawasaki T, Seki E, Osajima K, et al: Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. J Hum Hypertens 2000; 14: 519–523.
Hata Y, Yamamoto M, Ohni M, Nakashima K, Nakamura Y, Takano T : A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr 1996; 64: 767–771.
Fujita H, Yoshikawa M : LKPNM: a prodrug-type ACE inhibitory peptide derived from fish protein. Immunopharmacology 1999; 44: 123–127.
Takai S, Jin D, Sakaguchi M, Miyazaki M : Significant target organs for hypertension and cardiac hypertrophy by angiotensin-converting enzyme inhibitors. Hypertens Res 2004; 27: 213–219.
Matsui T, Hayashi A, Tamaya K, et al: Depressor effect induced by dipeptide, Val-Tyr, in hypertensive transgenic mice is due, in part, to the suppression of human circulating renin-angiotensin system. Clin Exp Pharm Physiol 2003; 30: 262–265.
Matsui T, Imamura M, Oka H, et al: Tissue distribution of antihypertensive dipeptide, Val-Tyr, after its single oral administration to spontaneously hypertensive rats. J Peptide Sci 2004; 10: 535–545.
Matsui T, Tamaya K, Seki E, Osajima K, Matsumoto K, Kawasaki T : Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system. Clin Exp Pharm Physiol 2002; 29: 204–208.
Masuda O, Nakamura Y, Takano T : Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr 1996; 126: 3063–3068.
Ishiyama M, Miyazono Y, Sasamoto K, Ohkura Y, Ueno K : A highly water-soluble disulfonated tetrazolium salt as a chromogenic indicator for NADH as well as cell viability. Talanta 1997; 44: 1299–1305.
Cheung H-S, Wang F-L, Ondetti MA, Sabo EF, Cushman DW : Binding of peptide substrates and inhibitors of angiotensin-converting enzyme. J Biol Chem 1980; 255: 401–407.
Matsufuji H, Matsui T, Ohshige S, Kawasaki T, Osajima K, Osajima Y : Antihypertensive effects of angiotensin fragments in SHR. Biosci Biotechnol Biochem 1995; 59: 1398–1401.
Dzau VJ, Safar ME : Large conduit arteries in hypertension: role of the vascular renin-angiotensin system. Circulation 1988; 77: 947–954.
Sato M, Ohsaki Y, Tobise K : Transforming growth factor-β1 proliferated vascular smooth muscle cells from spontaneously hypertensive rats. Am J Hypertens 1995; 8: 160–166.
Stepien O, Iouzalen L, Herembert T, Marche P : Amlodipine and vascular hypertrophy. Int J Cardiol 1997; 62: S79–S84.
Graf K, Xi X-P, Hsueh WA, Law RR : Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells. FEBS Lett 1997; 400: 119–121.
Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA : Angiotensin(1–7) inhibits vascular smooth muscle cell growth. Hypertension 1996; 28: 104–108.
Moon S-K, Cho G-O, Jung S-Y, et al: Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. Biochem Biophys Res Commun 2003; 301: 1069–1078.
Terano T, Tanaka T, Tamura Y, et al: Eiocosapentaenoic acid and docosahexaenoic acid inhibit vascular smooth muscle cell proliferation by inhibiting phosphorylation of Cdk2-cyclinE complex. Biochem Biophys Res Commun 1999; 254: 502–506.
Xu JW, Ikeda K, Yamori Y : Genistein inhibits expressions of NADPH oxidase p22phox and angiotensin II type 1 receptor in aortic endothelial cells from stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 675–683.
Awad BB, Smith AJ, Fink CS : Plant sterols regulate rat vascular smooth muscle cell growth and prostacyclin release in culture. Prostaglandins Leukot Essent Fatty Acids 2001; 64: 323–330.
Neves LAA, Averill DV, Ferrario CM, et al: Characterization of angiotensin-(1–7) receptor subtype in mesenteric arteries. Peptides 2003; 24: 455–462.
Watanabe T, Pakara R, Kataguri T, Benedict RC : Serotonin potentiates angiotensin II-induced vascular smooth muscle cell proliferation. Atherosclerosis 2001; 159: 269–279.
Min L, Sim MK, Xu XG : Effects of des-aspartate-angiotensin I on angiotensin II-induced incorporation of phenylalanine and thymidine in cultured rat cardiomyocytes and aortic smooth muscle cells. Regul Pept 2000; 95: 93–97.
Yoo HJ, Kozaki K, Akishita M, et al: Augmented Ca2+ influx is involved in the mechanism of enhanced proliferation of cultured vascular smooth muscle cells from spontaneously diabetic Goto-Kakizaki rats. Atherosclerosis 1997; 131: 167–175.
Umemoto S, Tanaka M, Kawahara S, Kubo M, Umeji K, Hashimoto R, Matsuzaki M : Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 877–885.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Matsui, T., Ueno, T., Tanaka, M. et al. 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. Hypertens Res 28, 545–552 (2005). https://doi.org/10.1291/hypres.28.545
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.28.545
Keywords
This article is cited by
-
Milk casein-derived tripeptides, VPP and IPP induced NO production in cultured endothelial cells and endothelium-dependent relaxation of isolated aortic rings
Heart and Vessels (2011)
-
Peptides fonctionnels marins
Phytothérapie (2007)