Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2399-408. doi: 10.1152/ajpheart.00238.2008. Epub 2008 Oct 17.


The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 microg/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and IkappaB-alpha after SAA treatment. Consequently, the antioxidants seleno-l-methionine and Mn(III) tetrakis-(4-benzoic acid)porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-kappaB. These findings suggest that SAA may contribute to the progress of coronary artery disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Bradykinin / metabolism
  • Catalase / metabolism
  • Cells, Cultured
  • Coronary Vessels / drug effects
  • Coronary Vessels / metabolism*
  • Coronary Vessels / physiopathology
  • Down-Regulation
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Humans
  • I-kappa B Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidative Stress
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / metabolism
  • Serum Amyloid A Protein / metabolism*
  • Signal Transduction
  • Superoxide Dismutase / metabolism
  • Swine
  • Time Factors
  • Vasodilation* / drug effects


  • Antioxidants
  • I-kappa B Proteins
  • NFKBIA protein, human
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Serum Amyloid A Protein
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide
  • Catalase
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Superoxide Dismutase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Bradykinin