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CLINICAL RESEARCH: ANTI-INFLAMMATORY THERAPY IN CORONARY ARTERY DISEASE

Potential anti-inflammatory role of activin A in acute coronary syndromes

Camilla Smith, MD^*, Arne Yndestad, MSc^*, Bente Halvorsen, MSc, PhD^*, Thor Ueland, BS^*, Torgun Wæhre, MD^*, Kari Otterdal, MSc^*, Hanne Scholz, MSc^*, Knut Endresen, MD, PhD, Lars Gullestad, MD, PhD^||, Stig S. Frøland, MD, PhD^*, Jan Kristian Damås, MD, PhD^* and Pål Aukrust, MD, PhD^*,*

^* Research Institute for Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
Section of Endocrinology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
^|| Department of Medicine, Bærum Hospital, Sandvika, Norway

Manuscript received December 16, 2003; revised manuscript received March 23, 2004, accepted April 3, 2004.

^* Reprint requests and correspondence: Dr. Pål Aukrust, Section of Clinical Immunology and Infectious Diseases, Medical Department, Rikshopitalet, Sognsvannsveien 20, 0027 Oslo, Norway.
pal.aukrust{at}rikshospitalet.no

OBJECTIVES: We sought to investigate whether activin A could be involved in the immunopathogenesis of acute coronary syndromes.

BACKGROUND: Inflammatory mechanisms seem to play a pathogenic role in atherosclerosis and acute coronary syndromes, but the actual mediators have not been fully identified. Activin A, a pleiotropic member of the transforming growth factor-beta cytokine family, has recently been suggested to play a role in inflammation.

METHODS: We examined the role of activin A and its endogenous inhibitor follistatin in patients with stable (n = 26) and unstable angina (n = 20) and healthy control subjects (n = 20) by different experimental approaches.

RESULTS: 1) Patients with stable angina had raised activin A concentrations, as assessed by protein levels in serum and messenger ribonucleic acid levels in peripheral blood mononuclear cells (PBMCs). 2) Although several activin A–related mediators were upregulated in PBMCs from patients with stable angina compared with controls (i.e., activin A and Smad3), no changes or even downregulation (i.e., Smad2) were seen in unstable disease. 3) The activin type II receptors, representing the primary ligand-binding proteins, were downregulated in unstable compared with stable angina. 4) Percutaneous coronary intervention induced a decrease in the activin A/follistatin ratio, suggesting downregulatory effects on activin A activity. 5) Although activin A dose-dependently suppressed the release of inflammatory cytokines from PBMCs in angina patients, an opposite effect was found in healthy controls.

CONCLUSIONS: Our findings suggest an anti-inflammatory potential of activin A in angina patients, and such effects may be of particular relevance in unstable angina in which several of the activin parameters were downregulated.

Abbreviations and Acronyms   CAD = coronary artery disease   EIA = enzyme immunoassay   IL = interleukin   MIP = macrophage inflammatory protein   mRNA = messenger ribonucleic acid   PBMC = peripheral blood mononuclear cell   PCI = percutaneous coronary intervention   TGF = transforming growth factor   TNF = tumor necrosis factor

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