TY - JOUR
T1 - Combined application of rapamycin and atorvastatin improves lipid metabolism in apolipoprotein E-deficient mice with chronic kidney disease
AU - Song, Eun Ju
AU - Ahn, Sanghyun
AU - Min, Seung Kee
AU - Ha, Jongwon
AU - Oh, Goo Taeg
N1 - Funding Information:
This study was supported by the Research Resettlement Fund for the new faculty of Seoul National University, a grant from the SNUH Research Fund (04-2016-0360), and a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2012R1A3A2026454). The funders and company had no role in study design, data collection, analysis, the decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright © 2021 by the The Korean Society for Biochemistry and Molecular Biology
PY - 2021
Y1 - 2021
N2 - Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE−/−) mice. Oil Red O staining revealed that treatment with RAPA and RAPA+ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXRα, CYP7A1, ABCG1, PPARγ, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosispromoting cytokines in the spleen (Tnf-α, Il-6 and Il-1β) and aorta (Tnf-α and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA+ATV decreased the levels of Tnf-α and Il-1β in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE−/−mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism. [BMB Reports 2021; 54(3): 170-175]
AB - Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE−/−) mice. Oil Red O staining revealed that treatment with RAPA and RAPA+ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXRα, CYP7A1, ABCG1, PPARγ, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosispromoting cytokines in the spleen (Tnf-α, Il-6 and Il-1β) and aorta (Tnf-α and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA+ATV decreased the levels of Tnf-α and Il-1β in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE−/−mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism. [BMB Reports 2021; 54(3): 170-175]
KW - Atherosclerosis
KW - Atorvastatin
KW - Chronic kidney disease
KW - Co-administration
KW - Rapamycin
UR - http://www.scopus.com/inward/record.url?scp=85103509398&partnerID=8YFLogxK
U2 - 10.5483/BMBRep.2021.54.3.136
DO - 10.5483/BMBRep.2021.54.3.136
M3 - Article
C2 - 33050984
AN - SCOPUS:85103509398
SN - 1976-6696
VL - 54
SP - 170
EP - 175
JO - BMB Reports
JF - BMB Reports
IS - 3
ER -