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

Xiaoping Cai,Ben Freedman,Yuyang Liu,Paul K Witting,Xiaosuo Wang,Gulfam Ahmad,Farjaneh Hossain,Joanne Dennis

doi:10.3390/ijms21041316

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.

Highlights

Endothelial dysfunction is a hallmark of atherosclerosis and represents an early event in developing cardiovascular disease (CVD)
Urinary kidney injury molecule (KIM)‐1 in the young cohort was significantly higher in Serum amyloid A (SAA)‐treated mice than that determined in urine samples from the control and LPS groups, as we described previously [35]
The relative levels of circulating high-density lipoprotein (HDL) and SAA may be important in determining risk of developing cardiovascular and renal disorders and interventional measures to increase HDL may limit the pro-inflammatory bioactivity of SAA in humans and decrease risk of developing these pathologies

Summary

Introduction

Endothelial dysfunction is a hallmark of atherosclerosis and represents an early event in developing cardiovascular disease (CVD). Perturbations of endothelial cell structure and function in acute and chronic inflammatory diseases can promote endothelial dysfunction, which is an early pathological process causally linked to the development of atherosclerosis [1,2], a process central to developing CVD. The potential for SAA to instigate endothelial [11,12,13] and renal dysfunction has been established [14] Taken together, these data suggest that SAA is not merely a biomarker of inflammation but that it stimulates cells through binding various surface receptors [15] to elicit pro-inflammatory and pro-thrombotic responses that can initiate the earliest stages of vascular disease and accelerate rates of CVD and renal disorders

Methods

Results

Discussion

Conclusion