Low-dosage statins reduce choroidal damage in hypercholesterolemic rabbits

Abstract

ABSTRACT.Purpose: To describe the ultrastructural changes in the choroid of long-term hypercholesterolemic rabbits after a low-dosage statin treatment and to evaluate some pleiotropic effects of these drugs on the morphology of endothelial cells (EC) and vascular smooth-muscle cells (VSMC). Methods: New Zealand rabbits were divided into three groups: G0, fed a standard diet; G1, fed a 0.5% cholesterol-enriched diet for 8 months and G2, fed a 0.5% cholesterol-enriched diet for 8 months plus administration of fluvastatin sodium or pravastatin sodium at a dose of 2 mg ⁄ Kg ⁄ day each. Eyes were processed for transmission-electron microscopy. Results: G1 had a lipid build-up at the suprachoroidea that compressed the vascular layers with the lumens of the vessels to the point of collapse in some instances. By contrast, G2 underwent a substantial decrease in suprachoroidal foam cells and of lipids in the vascular layers while the vascular lumens were normal. The preservation of cytoplasmic organelles, caveolar system and other ultrastructural features of EC and VSMC in G2 contrasted with the numerous signs of necrosis observed in G1. Bruch's membrane (BM) in G2 contained fewer lipids and more collagen than in G1. Conclusion: Treatment with a low dosage of fluvastatin sodium or pravastatin sodium reduced the lipid build-up as well as the macrophages in the choroid and restored the vascular lumens of choroidal vessels independently of the cholesterol effect. The normal ultrastructural features of choroidal EC and VSMC in statin-treated animals suggest that the endothelial function is preserved and the ischaemia reduced.

Choroidal Vessel Wall: Hypercholesterolaemia-Induced Dysfunction and Potential Role of Statins

“…Such effects have been demonstrated in rabbits fed cholesterol at a dose insufficient to reduce plasma-cholesterol levels [55,148].…”

“…iii) Finally, the intervascular spaces of the choroid contained fewer lipids than in hypercholesterolaemic animals but more collagen fibres than in control ( Figures 11A,C,12A,C). [6] and Rojas et al [55]). This increase in collagen fibres was also found in the intima, among VSMC and in the adventitia ( Figure 12C) of the large-and medium-sized-vessel layer and in the basal membrane of the EC of the choriocapillaris [6].…”

“…Other filaments are oriented towards thickenings of the cell membrane; the filaments join these thickenings in the same way as hemidesmosomes [15]. Alternating with the dense structures, rows of caveoles appear along the surface of the cell membrane [55]. The muscle cells are joined together by macular adherent junctions, punctiform junctions, and gap junctions [54] ( Figure 13A).…”

“…According with reference [148], hypercholesterolaemic rabbits treated with fluvastatin sodium and pravastatin sodium at a non-lipid-lowering dosage (2 mg/kg/day) showed a very small descent in plasma cholesterol and triglycerides levels [55]. In comparison with hypercholesterolaemic rabbits, low-dose statin-treated animals had far fewer lipids in the suprachoroid (the foam cells were decreased or absent), triggering a significant thinning of the sclera-suprachoroid complex (p< 0.000) (Figure 9).…”

“…These later pass through the membrane and make contact with the closest muscle cells. In the cytoplasm of the EC the normal organelles can be found: mitochondria, Golgi apparatus, rough endoplasmic reticulum, caveolar system, free polyribosomes, cytoplasmic vesicles and WeibelPalade bodies, which are membrane-bound granules containing an electrodense material [54,55]. The processes of the EC overlap and are joined together by different types of cell bonds: zonula adherens, tight junctions, and long gap junctions [38] ( Figure 13A).…”