Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation

Abstract

Objective-Proof of principle is presented for targeted enzyme supplementation by using lysosomal acid lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis. Methods and Results-Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. ␣-Mannosyl-terminated human lysosomal acid lipase (phLAL) was produced in Pichia pastoris, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages. A therosclerosis is the number 1 cause of mortality and morbidity in the developed countries. A number of interventions or preventions delay the consequences of atherosclerosis, eg, low cholesterol diet and exercise, HMG-CoA reductase inhibitors, and coronary artery bypass. However, they are not suitable for all patients, and few have been shown to promote regression of lesions. Therefore, new approaches are needed for the treatment and prevention of atherosclerosis. Several stages characterize the progression of atherosclerotic lesions. 1,2 The earliest lesion is the "fatty streak," an aggregation of lipid-rich macrophages and T-lymphocytes within the intimae layer of an artery. The fatty streaks evolve into intermediate lesions that have a layer of foamy macrophages and smooth muscle cells. This develops into complex and occlusive lesions, as well as fibrous plaques. These plaques have a dense cap of connective tissue, with embedded smooth muscle cells overlaying a core of lipid and necrotic debris. Macrophages are present at all lesional stages with excessive cholesterol and cholesteryl esters in lysosomes. Continuing development of atherosclerotic plaques requires progressive macrophage processing of cholesteryl esters in and through the lysosomes. Perpetuation and maturation of the plaques depends on additional complex inflammatory and scarring processes. Lysosomal acid lipase (LAL) is the only hydrolase for cleavage of cholesteryl esters delivered to the lysosomes. 3 The receptors that mediate cholesteryl ester uptake into macrophage include those for LDL and oxidized LDL (oxLDL), ie, LDL receptor (LDL-R), the scavenger receptors type AI and AII (SR-AI and SR-AII), 4 -6 the scavenger receptor type B1 (SR-BI), 7-9 CD36, 10 and the LDL receptor related protein (LRP). 11 All of these, except SR-BI, direct associated lipids to the lysosome. 12-15 Furthermore, modification of LDL by oxidation, aggregation, and glycation occurs in the atherosclerotic lesions by histochemical and biochemical studies. 16 -20 The delivery of oxidized LDL to lysosomes of macropha...

Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages

“…It is highly likely that interaction of macrophages with E 2 /B48 lipoproteins reduces the protein level of lysosomal hydrolases, which in turn reduces the degradation of the lipid and protein components of E 2 /B48 lipoproteins, leading to lipoprotein accumulation in the lysosomes and inducing foam cell formation. This presumption was supported by published evidence that superimposition of a lysosomal acid lipase mutation onto an ApoE-deficient background accelerated the development of atherosclerosis in mice (19), whereas intravenous administration of recombinant human lysosomal acid lipase into LDLR-deficient mice delayed the development of atherosclerotic lesions (20). Paradoxically, macrophages in the atherosclerotic lesions have been shown to increase the secretion of cathepsins in ApoE-deficient mice (21).…”

Age-Associated Aortic Stenosis in Apolipoprotein E-Deficient Mice

“…In most studies, atherosclerotic lesions in the aorta, coronary arteries, and pulmonary arteries were analyzed in the ApoEϪ/Ϫ mice up to 23 weeks of age (31,35,36). Although a few reports have described pathological changes in aortic valves of hypercholesterolemic mice (37,38), no physiological examination was performed to detect functional abnormalities in ApoEϪ/Ϫ mice. In this study, echocardiogram and histological examination successfully detected sclerotic changes with functional abnormality in the aortic valves of ApoEϪ/Ϫ mice of advanced age.…”

Molecular Biology of Atherosclerosis

“…Another model with LIPA deficiency in apo E KO mice may have had increased atherosclerosis but comparison with apo E KO alone not given (449).…”