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.