Combined application of rapamycin and atorvastatin improves lipid metabolism in apolipoprotein E-deficient mice with chronic kidney disease
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Atherosclerosis arising from the pro-inflammatory conditionsassociated with chronic kidney disease (CKD) increases majorcardiovascular morbidity and mortality. Rapamycin (RAPA) isknown to inhibit atherosclerosis under CKD and non-CKD conditions,but it can cause dyslipidemia; thus, the co-application oflipid-lowering agents is recommended. Atorvastatin (ATV) hasbeen widely used to reduce serum lipids levels, but its synergisticeffect with RAPA in CKD remains unclear. Here, we analyzedthe effect of their combined treatment on atherosclerosis stimulatedby CKD in apolipoprotein E-deficient (ApoE−/−) mice. OilRed O staining revealed that treatment with RAPA and RAPA＋ATV, but not ATV alone, significantly decreased the atheroscleroticlesions in the aorta and aortic sinus, compared to those seen inthe control (CKD) group. The co-administration of RAPA and ATVimproved the serum lipid profile and raised the expressionlevels of proteins involved in reverse cholesterol transport (LXR,CYP7A1, ABCG1, PPAR, ApoA1) in the liver. The CKD groupshowed increased levels of various genes encoding atherosclerosispromotingcytokines in the spleen (Tnf-, Il-6 and Il-1) and aorta(Tnf- and Il-4), and these increases were attenuated by RAPAtreatment. ATV and RAPA＋ATV decreased the levels of Tnf-and Il-1 in the spleen, but not in the aorta. Together, theseresults indicate that, in CKD-induced ApoE−/− mice, RAPA significantlyreduces the development of atherosclerosis by regulatingthe expression of inflammatory cytokines and the co-applicationof ATV improves lipid metabolism.
Abstract
Atherosclerosis arising from the pro-inflammatory conditionsassociated with chronic kidney disease (CKD) increases majorcardiovascular morbidity and mortality. Rapamycin (RAPA) isknown to inhibit atherosclerosis under CKD and non-CKD conditions,but it can cause dyslipidemia; thus, the co-application oflipid-lowering agents is recommended. Atorvastatin (ATV) hasbeen widely used to reduce serum lipids levels, but its synergisticeffect with RAPA in CKD remains unclear. Here, we analyzedthe effect of their combined treatment on atherosclerosis stimulatedby CKD in apolipoprotein E-deficient (ApoE−/−) mice. OilRed O staining revealed that treatment with RAPA and RAPA＋ATV, but not ATV alone, significantly decreased the atheroscleroticlesions in the aorta and aortic sinus, compared to those seen inthe control (CKD) group. The co-administration of RAPA and ATVimproved the serum lipid profile and raised the expressionlevels of proteins involved in reverse cholesterol transport (LXR,CYP7A1, ABCG1, PPAR, ApoA1) in the liver. The CKD groupshowed increased levels of various genes encoding atherosclerosispromotingcytokines in the spleen (Tnf-, Il-6 and Il-1) and aorta(Tnf- and Il-4), and these increases were attenuated by RAPAtreatment. ATV and RAPA＋ATV decreased the levels of Tnf-and Il-1 in the spleen, but not in the aorta. Together, theseresults indicate that, in CKD-induced ApoE−/− mice, RAPA significantlyreduces the development of atherosclerosis by regulatingthe expression of inflammatory cytokines and the co-applicationof ATV improves lipid metabolism.
참고문헌 (40)
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