High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice

Abstract

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.

Efficacy of the Piperidine Nitroxide 4-MethoxyTEMPO in Ameliorating Serum Amyloid A-Mediated Vascular Inflammation

“…Consistent with previous studies [8], NF-κB mRNA expression was 1.5-fold higher in cells exposed to SAA relative to the vehicle control after 6 h while co-administration…”

“…Consistent with previous studies [8], NF-κB mRNA expression was 1.5-fold higher in cells exposed to SAA relative to the vehicle control after 6 h while co-administration Images were captured using an inverted light microscope with 10× magnification. Insets to panels (A-C) show higher magnification images of cells across the corresponding treatment groups.…”

“…Previously, we [ 8 , 9 , 10 ] and others [ 11 , 12 , 13 , 14 , 15 ] have shown a relationship between higher SAA levels and vascular pathology implicated in atherosclerosis. Although, accumulating evidence suggests that elevated serum SAA levels are associated with promoting pathology, the data is inconclusive.…”

Connection between the Altered HDL Antioxidant and Anti‐Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review

“…The liver is the main site of SAA production, although stimulated monocytes/macrophages, vascular smooth muscle cells, and endothelial cells may locally secrete SAA during chronic inflammatory conditions. Plasma SAA concentrations can rise up to 1000-fold within 24 h when stimulated by the acute phase response, while modest increases of SAA levels (+10-fold) usually accompany chronic inflammatory disorders such as atherosclerosis [ 65 ].…”

“…This negative impact on HDL function seems related to the capacity of SAA to displace ApoA1 from HDLs [ 73 ]. On the other way around, HDLs are able to inhibit SAA proinflammatory, prooxidant and prothrombotic activities, as emerged from in vitro and preclinical studies [ 65 , 74 ].…”