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Inhibition of Inositol Monophosphatase by Lithium Chloride Induces Selective Macrophage Apoptosis in Atherosclerotic Plaques

Overview

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2010 Dec 9

PMID 21138421

Citations 15

Authors

Authors

Inge De Meyer

Wim Martinet

Cor E Van Hove

Dorien M Schrijvers

Vicky Y Hoymans

Luc Van Vaeck

Paul Fransen

Hidde Bult

Guido R Y De Meyer

Affiliations

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Lithium chloride (LiCl) inhibits inositol monophosphatase (IMPase) at therapeutic concentrations. Given that LiCl induces death in cultured macrophages and that macrophages play an active role in atherosclerotic plaque destabilization, we investigated whether LiCl would induce selective macrophage death to stabilize the structure of the plaque.

Experimental Approach: The effect of LiCl was assessed on macrophages and smooth muscle cells (SMCs) in culture, in isolated atherosclerotic carotid arteries from rabbits and after local in vivo treatment via osmotic minipumps to rabbits with collared atherosclerotic carotid arteries. In addition, in vitro experiments were performed to elucidate the mechanism of LiCl-induced macrophage death.

Key Results: In vitro, whereas SMCs were highly resistant, LiCl induced macrophage death characterized by externalization of phosphatidylserine, caspase-3 cleavage and DNA fragmentation, all indicative of apoptosis. LiCl reduced inositol-1,4,5-trisphosphate levels in macrophages. Moreover, the IMPase inhibitor L-690 330 as well as IMPase gene silencing induced macrophage apoptosis. Both in vitro treatment of rabbit atherosclerotic carotid arteries with LiCl and local in vivo administration of LiCl to the plaques decreased plaque macrophages through apoptosis, as shown by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL), without affecting SMCs. Vasomotor studies in vitro showed that LiCl did not affect the functionality of SMCs and endothelial cells.

Conclusions And Implications: LiCl selectively decreased the macrophage load in rabbit atherosclerotic plaques via IMPase inhibition without affecting the viability or functionality of SMCs and endothelial cells. These data provide evidence for local administration of an IMPase inhibitor to stabilize atherosclerotic plaques.

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References

1.

Back M, Ketelhuth D, Agewall S . Matrix metalloproteinases in atherothrombosis. Prog Cardiovasc Dis. 2010; 52(5):410-28. DOI: 10.1016/j.pcad.2009.12.002. View

2.

Ambrose J, Martinez E . A new paradigm for plaque stabilization. Circulation. 2002; 105(16):2000-4. DOI: 10.1161/01.cir.0000012528.89469.8e. View

3.

Pap M, Cooper G . Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem. 1998; 273(32):19929-32. DOI: 10.1074/jbc.273.32.19929. View

4.

Ward M, Pasterkamp G, Yeung A, Borst C . Arterial remodeling. Mechanisms and clinical implications. Circulation. 2000; 102(10):1186-91. DOI: 10.1161/01.cir.102.10.1186. View

5.

Phiel C, Klein P . Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 2001; 41:789-813. DOI: 10.1146/annurev.pharmtox.41.1.789. View

6.

Mikoshiba K, Furuichi T, Miyawaki A, Yoshikawa S, Nakade S, Michikawa T . Structure and function of inositol 1,4,5-trisphosphate receptor. Ann N Y Acad Sci. 1993; 707:178-97. DOI: 10.1111/j.1749-6632.1993.tb38052.x. View

7.

Boyle J, Weissberg P, Bennett M . Human macrophage-induced vascular smooth muscle cell apoptosis requires NO enhancement of Fas/Fas-L interactions. Arterioscler Thromb Vasc Biol. 2002; 22(10):1624-30. DOI: 10.1161/01.atv.0000033517.48444.1a. View

8.

Ohnishi T, Ohba H, Seo K, Im J, Sato Y, Iwayama Y . Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. J Biol Chem. 2006; 282(1):637-46. DOI: 10.1074/jbc.M604474200. View

9.

Lecoeur H, Ledru E, Prevost M, Gougeon M . Strategies for phenotyping apoptotic peripheral human lymphocytes comparing ISNT, annexin-V and 7-AAD cytofluorometric staining methods. J Immunol Methods. 1998; 209(2):111-23. DOI: 10.1016/s0022-1759(97)00138-5. View

10.

Cannon C, Braunwald E, McCabe C, Rader D, Rouleau J, Belder R . Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350(15):1495-504. DOI: 10.1056/NEJMoa040583. View

11.

Lubrich B, van Calker D . Inhibition of the high affinity myo-inositol transport system: a common mechanism of action of antibipolar drugs?. Neuropsychopharmacology. 1999; 21(4):519-29. DOI: 10.1016/S0893-133X(99)00037-8. View

12.

Vindelov L, Christensen I . Detergent and proteolytic enzyme-based techniques for nuclear isolation and DNA content analysis. Methods Cell Biol. 1994; 41:219-29. DOI: 10.1016/s0091-679x(08)61720-3. View

13.

Lowik C, Alblas M, Van de Ruit M, Papapoulos S, van der Pluijm G . Quantification of adherent and nonadherent cells cultured in 96-well plates using the supravital stain neutral red. Anal Biochem. 1993; 213(2):426-33. DOI: 10.1006/abio.1993.1442. View

14.

Klein P, Melton D . A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A. 1996; 93(16):8455-9. PMC: 38692. DOI: 10.1073/pnas.93.16.8455. View

15.

Stambolic V, Ruel L, Woodgett J . Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol. 1996; 6(12):1664-8. DOI: 10.1016/s0960-9822(02)70790-2. View

16.

Sarkar S, Floto R, Berger Z, Imarisio S, Cordenier A, Pasco M . Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005; 170(7):1101-11. PMC: 2171537. DOI: 10.1083/jcb.200504035. View

17.

Aikawa M, Rabkin E, Okada Y, Voglic S, Clinton S, Brinckerhoff C . Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation. 1998; 97(24):2433-44. DOI: 10.1161/01.cir.97.24.2433. View

18.

Berridge M, Downes C, Hanley M . Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989; 59(3):411-9. DOI: 10.1016/0092-8674(89)90026-3. View

19.

Lafont A . Basic aspects of plaque vulnerability. Heart. 2003; 89(10):1262-7. PMC: 1767898. DOI: 10.1136/heart.89.10.1262. View

20.

Kockx M, Herman A . Apoptosis in atherosclerosis: beneficial or detrimental?. Cardiovasc Res. 2000; 45(3):736-46. DOI: 10.1016/s0008-6363(99)00235-7. View