High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice
by
Xiaoping Cai 1,ā , Gulfam Ahmad 1,ā , Farjaneh Hossain 1
, Yuyang Liu 1, XiaoSuo Wang 1, Joanne Dennis 1, Ben Freedman 2 and Paul K. Witting 1,*
Xiaoping Cai 1,ā , Gulfam Ahmad 1,ā , Farjaneh Hossain 1, Yuyang Liu 1, XiaoSuo Wang 1, Joanne Dennis 1, Ben Freedman 2 and Paul K. Witting 1,*
1
Discipline of Pathology, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
2
Heart Research Institute, Charles Perkins Centre, and ANZAC Research University of Sydney, Sydney, NSW 2006, Australia
*
Author to whom correspondence should be addressed.
ā
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(4), 1316; https://doi.org/10.3390/ijms21041316
Received: 6 January 2020 / Revised: 9 February 2020 / Accepted: 11 February 2020 / Published: 15 February 2020
(This article belongs to the Special Issue High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad, and the Future)
Serum amyloid A (SAA) promotes endothelial inflammation and dysfunction that is associated with cardiovascular disease and renal pathologies. SAA is an apoprotein for high-density lipoprotein (HDL) and its sequestration to HDL diminishes SAA bioactivity. Herein we investigated the effect of co-supplementing HDL on SAA-mediated changes to vascular and renal function in apolipoprotein E-deficient (ApoE−/−) mice in the absence of a high-fat diet. Male ApoE−/− mice received recombinant human SAA or vehicle (control) by intraperitoneal (i.p.) injection every three days for two weeks with or without freshly isolated human HDL supplemented by intravenous (i.v.) injection in the two weeks preceding SAA stimulation. Aorta and kidney were harvested 4 or 18 weeks after commencement of treatment. At 4 weeks after commencement of treatment, SAA increased aortic vascular cell adhesion molecule (VCAM)-1 expression and F2-isoprostane level and decreased cyclic guanosine monophosphate (cGMP), consistent with SAA stimulating endothelial dysfunction and promoting atherosclerosis. SAA also stimulated renal injury and inflammation that manifested as increased urinary protein, kidney injury molecule (KIM)-1, and renal tissue cytokine/chemokine levels as well as increased protein tyrosine chlorination and P38 MAPkinase activation and decreased in Bowman’s space, confirming that SAA elicited a pro-inflammatory phenotype in the kidney. At 18 weeks, vascular lesions increased significantly in the cohort of ApoE−/− mice treated with SAA alone. By contrast, pretreatment of mice with HDL decreased SAA pro-inflammatory activity, inhibited SAA enhancement of aortic lesion size and renal function, and prevented changes to glomerular Bowman’s space. Taken together, these data indicate that supplemented HDL reduces SAA-mediated endothelial and renal dysfunction in an atherosclerosis-prone mouse model.
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MDPI and ACS Style
Cai, X.; Ahmad, G.; Hossain, F.; Liu, Y.; Wang, X.; Dennis, J.; Freedman, B.; Witting, P.K. High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice. Int. J. Mol. Sci. 2020, 21, 1316.
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