Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemia
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Monocytes/macrophages are key players throughout atheroma development. The aim of this study was to determine the role of macrophages in lesion formation in heart valves in hyperlipidemia. We examined whether systemic depletion of monocytes/macrophages had a beneficial or adverse effect on the development of lesions in hyperlipemic hamsters injected twice weekly (for 2 months) with clodronate-encapsulated liposomes (H+Lclod), a treatment that selectively induces significant monocyte apoptosis. Hyperlipemic hamsters were employed as controls, as were hyperlipemic hamsters treated with plain liposomes. We assayed serum cholesterol (CH) and triglycerides (TG), the lipid and collagen contents and the size of the valve lesions, the matrix metalloproteinases (MMPs) in the serum and vessel wall, apolipoprotein E (ApoE), interleukin-1β (IL-1β), and superoxide anion production. In comparison with controls, H+Lclod hamsters exhibited: (1) increased lipid and collagen accumulation within the lesions, (2) decreased activity of MMP-9 and MMP-2 in sera and aortic homogenates, (3) decreased serum CH and TG and decreased expression of ApoE in sera and liver, (4) reduced expression of IL-1β in aorta and liver homogenates, and (5) no change in the level of superoxide anion in the aorta. Thus, initially, the presence of the macrophages is beneficial in valvular lesion formation. Depletion of monocytes/macrophages is a two-edged sword having a beneficial effect by decreasing the expression of IL-1β and MMP activities but an adverse effect by inducing a significant increase in the lipid and collagen content and expansion of valvular lesions.
KeywordsAortic valve Atherosclerosis Liposomes Clodronate Macrophages Hamster (Golden Syrian)
The authors are indebted to Gabriela Mesca, Rodica Tatia, Ana Manole, Safta Nae, Nicoleta Dobre, and Marilena Daju for technical assistance and to Dr. Adrian Manea for help with the determination of the superoxide anion.
- Danenberg HD, Fishbein I, Epstein H, Waltenberger J, Moerman E, Monkkonen J, Gao J, Gathi I, Reichi R, Golomb G (2003) Systemic depletion of macrophages by liposomal bisphosphonates reduces neointimal formation following balloon-injury in the rat carotid artery. J Cardiovasc Pharmacol 42:671–679PubMedCrossRefGoogle Scholar
- Gawaz M, Brand K, Dickfeld T, Pogatsa-Murray G, Page S, Bogner C, Koch W, Schomig A, Neumann F (2000) Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism: implications for atherogenesis. Atherosclerosis 148:75–85PubMedCrossRefGoogle Scholar
- Kanters E, Pasparakis M, Gijbels MJ, Vergouwe MN, Partouns-Hendriks I, Fijneman RJ, Clausen BE, Forster BE, Kockx MM, Rajewsky K, Kraal G, Hofker MH, Winter MP de (2003) Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest 112:1176–1185PubMedGoogle Scholar
- Lillie RD, Ashburn LL (1943) Supersaturated solutions of fat stains in dilute isopropanol for demonstration of acute fatty degeneration not shown by Herxheimer’s technique. Arch Pathol 36:432Google Scholar
- Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC (2002) Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 105:2260–2265CrossRefGoogle Scholar
- Sheehan D, Hrapchak B (1980) Theory and practice of histotechnology, 2nd edn. Battelle, Ohio, pp 189–190Google Scholar
- Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M (1986) Prelesional events in atherogenesis: accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol 123:1109–1125Google Scholar
- Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Böhm M, Meinertz T, Münzel T (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis:evidence for involvement of the renin-angiotensin system. Circulation 99:2027–2033PubMedGoogle Scholar