Abstract
Intracellular redox imbalance in endothelial cells (EC) can lead to endothelial dysfunction, which underpins cardiovascular diseases (CVD). The acute phase serum amyloid A (SAA) elicits inflammation through stimulating production of reactive oxygen species (ROS). The cyclic nitroxide 4-MethoxyTEMPO (4-MetT) is a superoxide dismutase mimetic that suppresses oxidant formation and inflammation. The aim of this study was to investigate whether 4-MetT inhibits SAA-mediated activation of cultured primary human aortic EC (HAEC). Co-incubating cells with 4-MetT inhibited SAA-mediated increases in adhesion molecules (VCAM-1, ICAM-1, E-selectin, and JAM-C). Pre-treatment of cells with 4-MetT mitigated SAA-mediated increases in transcriptionally activated NF-κB-p65 and P120 Catenin (a stabilizer of Cadherin expression). Mitochondrial respiration and ROS generation (mtROS) were adversely affected by SAA with decreased respiratory reserve capacity, elevated maximal respiration and proton leakage all characteristic of SAA-treated HAEC. This altered respiration manifested as a loss of mitochondrial membrane potential (confirmed by a decrease in TMRM fluorescence), and increased mtROS production as assessed with MitoSox Red. These SAA-linked impacts on mitochondria were mitigated by 4-MetT resulting in restoration of HAEC nitric oxide bioavailability as confirmed by assessing cyclic guanosine monophosphate (cGMP) levels. Thus, 4-MetT ameliorates SAA-mediated endothelial dysfunction through normalising EC redox homeostasis. Subject to further validation in in vivo settings; these outcomes suggest its potential as a therapeutic in the setting of cardiovascular pathologies where elevated SAA and endothelial dysfunction is linked to enhanced CVD.
Highlights
Acute phase response (APR) is a key component of the inflammatory response [1,2]and involves sequential physiological changes to combat inflammation, trauma or injury to host tissue [3]
During an APR, the body responds to maintain the internal equilibrium by metabolic and hormonal changes and among such adaptations, the regulation of plasma protein levels are of great significance
C reactive protein (CRP) is used as non-specific inflammatory marker for cardiovascular diseases [5], the biology and role of serum amyloid A (SAA) is less known
Summary
Acute phase response (APR) is a key component of the inflammatory response [1,2]. and involves sequential physiological changes to combat inflammation, trauma or injury to host tissue [3]. WWhheenn cceellllss wweerree pprree--ttrreeaatteeddwwiitthh44--MMeettTT,, SSAAAA ssttiimmuullaatteedd VVCCAAMM--11 pprrootteeiinn eexxpprreessssiioonn wwaass ssiiggnniiffiiccaannttllyy rreedduucceeddbbootthhaatt 66 aanndd 1122 hh ttiimmee ppooiinnttss wwhhiicchh ccoorrrreessppoonnddeedd cclloosseellyy ttoo mmRRNNAA eexxpprreessssiioonn ddaattaa iinnddiiccaattiinngg ththaatt4-4M-MeteTtTtretaretmatemnetnetffeecffteivcetilvyeilnyhiibnihteibditVeCdAVMC-A1Mge-n1egeexnpereesxsiporne.sTsihouns., 4-MetT minimised the impact of proatherogenic vascular cell adhesion in cells co-incubated with SAA and the nitroxide. Cells treated with SAA alone showed reduced mitochondrial potential relative to control as early as 1 h of incubation which was improved in cells pre-treated with 4-MetT (Figure 7A) as indicated in fluorescent microscopic images. Cells treated with SAA alone showed reduced mitochondrial potential relative to control as early as 1 h of in1c.5ubation which *w***as improved in cells pretreated with 4-MetT (Figure 7A) as indicated in fluorescent microsco*p* ic images. IInnddiivviidduuaall NNAADDPP((++))((CC))..IInnddiivviidduuaallNNAADDPP((HH))..nn ==33SSAAAA((22hh)),,SSAAAA((22hh))++44--MMeettTT,,nn ==66aallllootthheerrggrroouuppss.. * Differeenntt ttoo ccoonnttrroolliinntthheeaabbsseenncceeooffSSAAAA;;**pp
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