doi: 10.1161/01.ATV.0000252709.13329.7c
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Letter to the Editor |
Letter to the Editor
Monocyte cAMP Content Is Decreased in Patients With Stable Angina
From the Laboratorio de Cardiología Experimental (Lab 5), Medicina y Cirugía Experimentales and Hospital Clínico San Carlos, Prof Martín Lagos, 28040 Madrid, Spain.
Correspondence to Panayotis Fantidis, MD, C/ Los Arcos 3, Esc Cent. 2° 4, 28033 Madrid, Spain. Email pfantidis{at}yahoo.es
A crucial event in atherosclerosis is the formation of foam cells. Vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), macrophage chemoattractant protein-1 (MCP-1), and macrophage colony stimulating factor (M-CSF) are important molecules that contribute to foam cell formation.1 Removal of excess free cholesterol from macrophages, neutralization of monocyte migration inhibitory factor (MIF), and reduction of proinflammatory cytokine concentrations are important goals for the prevention of foam cell formation and the development of atherosclerosis.2,3
Increases in intracellular cAMP concentration inhibit the expression of ICAM-1 and VCAM-1,4 decrease the production of MCP-15 and M-CSF,6 increase the expression of antiinflammatory cytokines, and decrease the expression of MIF and proinflammatory interleukins.7 In addition, cAMP analogs induce the ABCA1 secretory pathway, by which apolipoproteins (apoA-I) actively remove free cholesterol from cells; treatment of macrophages with cAMP analogs causes parallel increases in apo-I–mediated cholesterol efflux.8
On the basis of the role of cAMP in the expression of proatherogenic and antiatherogenic molecules, we postulated that the intracellular cAMP concentrations of peripheral monocytes may be low in patients with coronary artery disease.
We studied 80 patients with chronic stable angina (SA) who were consecutively admitted to our hospital, and 67 healthy age-matched healthy volunteers with no known coronary artery disease or risk factors. Coronary angiography was carried out with all patients
Total plasma cholesterol (mg/dL), LDL-cholesterol (mg/dL), and HDL-cholesterol (mg/dL) were measured by colorimetric methods (Sigma Diagnostics Inc). Serum interleukin (IL)-6 (pg/mL) was measured by enzyme immunoassay (EIA; Diagnostic Products Corporation).
Peripheral blood mononuclear cells were separated from whole blood by density-gradient centrifugation on Ficoll-Paque columns, and monocytes were isolated by magnetic separation technology (MACS, Miltenyi Biotec GmbH). Monocytes were resuspended in RPMI-1640 (Gibco) containing 10% fetal bovine serum and 10% pooled normal human serum, and were then counted in a Neubauer chamber and stored at –80°C. The monocyte pellet was lysed ultrasonically for 180 seconds, and the intracellular levels of cAMP (pmol/106 cells) were measured by ELISA (Cayman Chemical R&D Systems Europe; the intra-and interassay coeficient of variations have been determined at multiple points of the curve. The coefficient variation is less than 5% in the 0.2 to 10 pmol/mL range). The kit instructions were followed.
Itracellular cAMP values (mean±SD) were analyzed by the 2-tailed test for unpaired observations. The null hypothesis was rejected when P
0.05.
The clinical characteristics of the patients at the time of admission are presented in the Table. Intracellular cAMP concentrations were significantly higher (P=0.001) in controls compared with SA patients (controls, 0.28±0.15 pmol/106 cells; and SA patients, 0.13±0.02 pmol/106 cells).
|
Previous studies reported that cellular cAMP content may have an important protective role, impeding the formation of atherosclerotic lesions,4–8 and that high cellular cAMP may promote reendothelialization, maintain endothelial cell function, and prevent the induction of procoagulant activity in response to certain cytokines.9,10 Indeed, cAMP enhancer drugs relieve the symptoms of patients with intermittent claudication, significantly increasing walking distances compared with placebo,11 improve serum lipid profile,12 reduce the incidence of atherosclerosis in mice,13 and suppress apoptosis.14 Furthermore, C-reactive protein reduced the antiinflammatory IL-10 production in human macrophages via inhibition of cAMP production.15
Intracellular cAMP concentration is determined by stimulation of adenylyl cyclase and by intracellular breakdown of this nucleotide by phosphodiesterases. The present work is a small preliminary study, and it was beyond of the scope of the study to assess whether adenylyl cyclase is inhibited, or the phosphodiesterases are activated in subjects that develop coronary artery disease. However, our results provide the first demonstration that monocyte cAMP content is decreased in patients with SA, suggesting new ways to evaluate the role of cellular cAMP content in the development of atherosclerosis.
Acknowledgments
Sources of Funding
This study was supported by grants from Comunidad Autónoma de Madrid (No. 8.4/001) and Sociedad Española de Cardiología.
Disclosures
None.
References
- Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
[Free Full Text] - Oram JF. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Arterioscler Thromb Vasc Biol. 2003; 23: 720–727.
[Abstract/Free Full Text] - Schober A, Bemhagen J, Thiele M, Zeiffer U, Knarren S, Roller M, Bucala R, Weber C. Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice. Circulation. 2004; 109: 380–385.
- Braun M, Pietsch P, Zepp A, Schror K, Baumann G, Felix SB. Regulation of tumor necrosis factor alpha- and IL-1-beta-induced adhesion molecule expression in human vascular smooth muscle cells by cAMP. Arterioscler Thromb Vasc Biol. 1997; 17: 2568–2575.
[Abstract/Free Full Text] - Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM. Modulation by cAMP of IL-1 beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells. Eur Respir J. 2003; 22: 220–226.
[Abstract/Free Full Text] - Kamthong PJ, Wu MC. Inhibitor of nuclear-
B induction by cAMP antagonizes interlukin-1-induced human macropahge-colony-stimulating-factor expression. Biochem J. 2001; 356: 525–530.[CrossRef][Medline]
[Order article via Infotrieve] - Zidek Z. Adenosine: cyclic AMP pathways and cytokine expression. Eur Cytokine Netw. 1999; 10: 319–328.[Medline] [Order article via Infotrieve]
- Haider B, Denis M, Marcil M, Krimbou L, Genest J Jr. Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter. J Biol Chem. 2004; 279: 9963–9969.
[Abstract/Free Full Text] - Fantidis P, Fernanadez-Ortiz A, Aragoncillo P, Pérex de Prada T, Sanmartín M, López J, Sabaté M, Escaned J, Alfonso F, Hernández R, Bañuelos C, Macaya C. Effect of cAMP on the function of endothelial cells and fibromuscular proliferation after injury of carotid and coronary arteries in a porcine model. Rev Esp Cardiol. 2001; 54: 981–989.[Medline] [Order article via Infotrieve]
- Ogawa S, Gerlach H, Esposito C, Pasagian-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium: increased monolayer permeability and induction of procoagulant properties. J Clin Invest. 1990; 85: 1090–1098.[Medline] [Order article via Infotrieve]
- Jacoby D, Mohler ER 3rd. Drug treatment of intermittent claudication. Drugs. 2004; 64: 1657–1670.[CrossRef][Medline] [Order article via Infotrieve]
- Nakamura N, Osawa H, Yamabe H, Okumura K, Hamazaki T. Effects of cilostazol on lipid fatty acid metabolism, Clin Exp Med. 2005; 4: 170–173.[CrossRef][Medline] [Order article via Infotrieve]
- Lee HJ, Oh GT, Park SY, Choi JH, Park JG, Kim CD, Lee WS, Rhim BY, Shin YW, Hong KW. Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol. J Pharmacol Exp Ther. 2005; 313: 502–509.
[Abstract/Free Full Text] - Shin HK, Kim YK, Lee JH, Hong KW. Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of supoeroxide and cytokines via lectin-like oxidized low-density lipoprotein receptor. 1 activation: prevention by cilostazol, Circulation. 2004; 109: 1022–1028.
- Singh U, Devaraj S, Dasu MR, Ciobanu D, Reusch J, Jialal I. C-reactive protein decreases IL-10 secretion in activated human monocyte-derived macrophages via inhibition of cyclic AMP production. Arterioscler Thromb Vasc Biol. 2006; 26: 2469–2675.
[Abstract/Free Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||