Abstract
Elevated serum amyloid A (SAA) levels may promote endothelial dysfunction, which is linked to cardiovascular and renal pathologies. We investigated the effect of SAA on vascular and renal function in apolipoprotein E-deficient (ApoE−/−) mice. Male ApoE−/− mice received vehicle (control), low-level lipopolysaccharide (LPS), or recombinant human SAA by i.p. injection every third day for 2 weeks. Heart, aorta and kidney were harvested between 3 days and 18 weeks after treatment. SAA administration increased vascular cell adhesion molecule (VCAM)-1 expression and circulating monocyte chemotactic protein (MCP)-1 and decreased aortic cyclic guanosine monophosphate (cGMP), consistent with SAA inhibiting nitric oxide bioactivity. In addition, binding of labeled leukocytes to excised aorta increased as monitored using an ex vivo leukocyte adhesion assay. Renal injury was evident 4 weeks after commencement of SAA treatment, manifesting as increased plasma urea, urinary protein, oxidized lipids, urinary kidney injury molecule (KIM)-1 and multiple cytokines and chemokines in kidney tissue, relative to controls. Phosphorylation of nuclear-factor-kappa-beta (NFκB-p-P65), tissue factor (TF), and macrophage recruitment increased in kidneys from ApoE−/− mice 4 weeks after SAA treatment, confirming that SAA elicited a pro-inflammatory and pro-thrombotic phenotype. These data indicate that SAA impairs endothelial and renal function in ApoE−/− mice in the absence of a high-fat diet.
Highlights
IntroductionEndothelial cell (EC) dysfunction, characterized by altered nitric oxide (NO) production/bioactivity, precedes atherosclerosis [2], essential hypertension [3], and related cardiovascular disease (CVD)
A functional endothelium is vital for maintenance of vascular homeostasis [1]
The endogenous enzymic antioxidant catalase (CAT), but not glutathione peroxidase-1 (GPx-1) mRNA was significantly increased in aortae both were elevated in renal tissue 4 weeks after commencement of Serum amyloid A (SAA) treatment (Table 1)
Summary
Endothelial cell (EC) dysfunction, characterized by altered nitric oxide (NO) production/bioactivity, precedes atherosclerosis [2], essential hypertension [3], and related cardiovascular disease (CVD). Endothelium-derived NO is produced via the action of endothelial nitric oxide synthase (eNOS) on L-arginine (L-Arg), regulates vascular tone [4], and interactions between platelets [5], leukocytes [6], and the endothelium as well as modulating vascular smooth muscle cell (VSMC) proliferation [7]. Serum amyloid A (SAA) is a family of acute phase apo-lipoproteins, principally produced by hepatocytes and macrophages. SAA levels are elevated in chronic vascular diseases [9] and predict CVD risk [10, 11]. SAA gene transcription is mediated by SAA-activating sequence binding factor, NFκB, NF-IL-6, and Sp1 [12]
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