Skip to main content
Top
Published in: BMC Cardiovascular Disorders 1/2004

Open Access 01-12-2004 | Research article

The influence of statins on the free intracellular calcium concentration in human umbilical vein endothelial cells

Authors: Stephan Heinke, Gero Schwarz, Hans R Figulla, Stefan H Heinemann

Published in: BMC Cardiovascular Disorders | Issue 1/2004

Login to get access

Abstract

Background

Statins are cholesterol-lowering drugs that are widely used to reduce the risk of cardiac infarction. Their beneficial clinical effects, however, are not restricted to their influence on cholesterol production. As several studies have shown that they have a potency of relaxing blood vessels.

Methods

We measured the effects of statins on the intracellular free calcium concentration ([Ca2+]i) in human umbilical vein endothelial cells (HUVEC) after acute application and 24-h-preincubation of statins.

Results

Incubation of the cells for 24 h with cerivastatin or fluvastatin significantly increased the resting [Ca2+]i. For cerivastatin this effect manifested at a concentration of 1 μM. Increase of resting [Ca2+]i in the presence of cerivastatin also occurred when the nitric oxide synthase was inhibited. Transient Ca2+ release induced by histamine was not affected.

Conclusions

The increase of resting [Ca2+]i after incubation with cerivastatin or fluvastatin may provide an explanation for the direct effects of statins on the endothelial-dependent vasodilatation and restoration of endothelial activity in vivo.
Appendix
Available only for authorised users
Literature
1.
go back to reference Alvarez de Sotomayor M, Herrera MD, Marhuenda E, Andriantsitohaina R: Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat. Br J Pharmacol. 2000, 131: 1179-1187.CrossRefPubMedPubMedCentral Alvarez de Sotomayor M, Herrera MD, Marhuenda E, Andriantsitohaina R: Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat. Br J Pharmacol. 2000, 131: 1179-1187.CrossRefPubMedPubMedCentral
2.
go back to reference Boer R, Ulrich WR, Klein T, Mirau B, Haas S, Baur I: The inhibitory potency and selectivity of arginine substrate site nitric-oxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes. Mol Pharmacol. 2000, 58 (5): 1026-34.PubMed Boer R, Ulrich WR, Klein T, Mirau B, Haas S, Baur I: The inhibitory potency and selectivity of arginine substrate site nitric-oxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes. Mol Pharmacol. 2000, 58 (5): 1026-34.PubMed
3.
go back to reference Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1998, 95: 8880-8885. 10.1073/pnas.95.15.8880.CrossRefPubMedPubMedCentral Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1998, 95: 8880-8885. 10.1073/pnas.95.15.8880.CrossRefPubMedPubMedCentral
4.
go back to reference Fleming I, Busse R: Signal transduction of eNOS activation. Cardiovasc Res. 1999, 43: 532-541. 10.1016/S0008-6363(99)00094-2.CrossRefPubMed Fleming I, Busse R: Signal transduction of eNOS activation. Cardiovasc Res. 1999, 43: 532-541. 10.1016/S0008-6363(99)00094-2.CrossRefPubMed
5.
go back to reference Govers R, Rabelink TJ: Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol. 2001, 280: F193-206.PubMed Govers R, Rabelink TJ: Cellular regulation of endothelial nitric oxide synthase. Am J Physiol Renal Physiol. 2001, 280: F193-206.PubMed
6.
go back to reference Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985, 260: 3440-3450.PubMed Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985, 260: 3440-3450.PubMed
7.
go back to reference Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998, 101: 2711-2719.CrossRefPubMedPubMedCentral Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998, 101: 2711-2719.CrossRefPubMedPubMedCentral
8.
go back to reference Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW: Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. Am Coll Cardiol. 1999, 33: 234-241. 10.1016/S0735-1097(98)00514-2.CrossRef Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW: Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. Am Coll Cardiol. 1999, 33: 234-241. 10.1016/S0735-1097(98)00514-2.CrossRef
9.
go back to reference Laufs U, la Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998, 97: 1129-1135.CrossRefPubMed Laufs U, la Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998, 97: 1129-1135.CrossRefPubMed
10.
go back to reference Laufs U, Liao JK: Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998, 273: 24266-24271. 10.1074/jbc.273.37.24266.CrossRefPubMed Laufs U, Liao JK: Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998, 273: 24266-24271. 10.1074/jbc.273.37.24266.CrossRefPubMed
11.
go back to reference Mak DO, McBride S, Foskett JK: Inositol 1,4,5-trisphosphate activation of inositol trisphosphate receptor Ca2+ channel by ligand tuning of Ca2+ inhibition. Proc Natl Acad Sci U S A. 1999, 95 (26): 15821-5. 10.1073/pnas.95.26.15821.CrossRef Mak DO, McBride S, Foskett JK: Inositol 1,4,5-trisphosphate activation of inositol trisphosphate receptor Ca2+ channel by ligand tuning of Ca2+ inhibition. Proc Natl Acad Sci U S A. 1999, 95 (26): 15821-5. 10.1073/pnas.95.26.15821.CrossRef
12.
go back to reference Mizuno O, Kobayashi S, Hirano K, Nishimura J, Kubo C, Kanaide H: Stimulus-specific alteration of the relationship between cytosolic Ca2+ transients and nitric oxide production in endothelial cells ex vivo. Br J Pharmacol. 2000, 130: 1140-1146.CrossRefPubMedPubMedCentral Mizuno O, Kobayashi S, Hirano K, Nishimura J, Kubo C, Kanaide H: Stimulus-specific alteration of the relationship between cytosolic Ca2+ transients and nitric oxide production in endothelial cells ex vivo. Br J Pharmacol. 2000, 130: 1140-1146.CrossRefPubMedPubMedCentral
13.
14.
go back to reference O'Driscoll G, Green D, Taylor RR: Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997, 95: 1126-1131.CrossRefPubMed O'Driscoll G, Green D, Taylor RR: Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997, 95: 1126-1131.CrossRefPubMed
15.
go back to reference Sacks FM, Pfeffer MA, Moye LA: The effect of Pravastatin on coronary events after myocardial infarction in patient with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.CrossRefPubMed Sacks FM, Pfeffer MA, Moye LA: The effect of Pravastatin on coronary events after myocardial infarction in patient with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.CrossRefPubMed
16.
go back to reference Shepherd J, Cobbe SM, Ford I: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West Of Scotland Coronary Study Group. N Engl J Med. 1995, 333: 1301-1307. 10.1056/NEJM199511163332001.CrossRefPubMed Shepherd J, Cobbe SM, Ford I: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West Of Scotland Coronary Study Group. N Engl J Med. 1995, 333: 1301-1307. 10.1056/NEJM199511163332001.CrossRefPubMed
17.
go back to reference Volk T, Mading K, Hensel M, Kox WJ: Nitric oxide induces transient Ca2+ changes in endothelial cells independent of cGMP. J Cell Physiol. 1997, 172: 296-305. 10.1002/(SICI)1097-4652(199709)172:3<296::AID-JCP3>3.0.CO;2-J.CrossRefPubMed Volk T, Mading K, Hensel M, Kox WJ: Nitric oxide induces transient Ca2+ changes in endothelial cells independent of cGMP. J Cell Physiol. 1997, 172: 296-305. 10.1002/(SICI)1097-4652(199709)172:3<296::AID-JCP3>3.0.CO;2-J.CrossRefPubMed
18.
go back to reference Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M: Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000, 20: 61-69.CrossRefPubMed Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M: Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000, 20: 61-69.CrossRefPubMed
19.
go back to reference Yamada M, Huang Z, Dalkara T, Endres M, Laufs U, Waeber C, Huang PL, Liao JK, Moskowitz MA: Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000, 20: 709-717.CrossRefPubMed Yamada M, Huang Z, Dalkara T, Endres M, Laufs U, Waeber C, Huang PL, Liao JK, Moskowitz MA: Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000, 20: 709-717.CrossRefPubMed
Metadata
Title
The influence of statins on the free intracellular calcium concentration in human umbilical vein endothelial cells
Authors
Stephan Heinke
Gero Schwarz
Hans R Figulla
Stefan H Heinemann
Publication date
01-12-2004
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2004
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/1471-2261-4-4

Other articles of this Issue 1/2004

BMC Cardiovascular Disorders 1/2004 Go to the issue