(Circulation. 1999;100:1983-1991.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic
Role of Tumor Necrosis Factor-
From the Salvatore Maugeri Foundation, Institute for Care and Research, Cardiovascular Pathophysiology Research Centre (L.A., T.B., G.G., L.C.), and the Departments of Cardiology (S.C., P.B.), Statistics (G.P.), and Pathologic Anatomy (M.C., P.G.G.), University of Brescia; the Immunology Department, Spedali Civili, Brescia (F.M.); the Cardiology Department, Gussago, Brescia (M.V.); and the Department of Cardiology, University of Ferrara (R.F.), Italy.
Correspondence to Prof Roberto Ferrari, Cardiovascular Pathophysiology Research Center, Salvatore Maugeri Foundation, Via Pinidolo, 23, 25064 Gussago, Brescia, Italy. E-mail ferrari{at}master.cci.unibs.it
Background—Cytokine activation and endothelial dysfunction are typical phenomena of congestive heart failure (CHF). We tested the hypothesis that incubating human umbilical vein endothelial cells with serum from patients with CHF will downregulate endothelial constitutive nitric oxide synthase (eNOS) and induce apoptosis.
Methods and Results—We studied 21 patients with severe CHF.
Levels of tumor necrosis factor-
(TNF-) and several
neuroendocrine parameters were assessed. eNOS was measured
by Western Blot analysis and apoptosis by optical
microscopy and flow cytometry. We observed (1) eNOS downregulation
(difference versus healthy subjects at 24 hours
[P<0.05] and 48 hours [P<0.001]),
(2) nuclear morphological changes typical of apoptosis; and (3)
a high apoptotic rate with propidium iodide (increasing from
2.1±0.4% to 11.3±1.2% at 48 hours; P<0.001 versus
healthy subjects) and annexin V. An anti-human TNF- antibody did not
completely counteract these effects. A strong correlation existed
between eNOS downregulation and apoptosis
(r=-0.89; P<0.001).
Conclusions—Serum from patients with severe CHF downregulates
eNOS expression and increases apoptosis. High levels of TNF-
likely play a role, but they cannot be the only factor responsible.
Key Words: heart failure • tumor necrosis factor • endothelium • nitric oxide synthase • apoptosis
This article has been cited by other articles:
 |
|
 |
|
  J.-Y. Park, I. K. G. Farrance, N. M. Fenty, J. M. Hagberg, S. M. Roth, D. M. Mosser, M. Q. Wang, H. Jo, T. Okazaki, S. R. Brant, et al. NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2320 - H2327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-H. Jung, K. Chu, S.-T. Lee, S.-J. Kim, E.-C. Song, E.-H. Kim, D.-K. Park, D.-I. Sinn, J.-M. Kim, M. Kim, et al. Blockade of AT1 Receptor Reduces Apoptosis, Inflammation, and Oxidative Stress in Normotensive Rats with Intracerebral Hemorrhage J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1051 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Goodwin, L. C. Pendleton, M. M. Levy, L. P. Solomonson, and D. C. Eichler Tumor necrosis factor-{alpha} reduces argininosuccinate synthase expression and nitric oxide production in aortic endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1115 - H1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ceconi, K. M. Fox, W. J. Remme, M. L. Simoons, M. Bertrand, G. Parrinello, C. Kluft, A. Blann, D. Cokkinos, and R. Ferrari ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT Cardiovasc Res, January 1, 2007; 73(1): 237 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Hoare, E. J. Birks, C. Bowles, N. Marczin, and M. H. Yacoub In vitro endothelial cell activation and inflammatory responses in end-stage heart failure J Appl Physiol, November 1, 2006; 101(5): 1466 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Williams, A. Verhovez, A. Milan, F. Veglio, and P. Mulatero Protective Effect of Spironolactone on Endothelial Cell Apoptosis Endocrinology, May 1, 2006; 147(5): 2496 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang and X.-F. Ming Recent advances in understanding endothelial dysfunction in atherosclerosis. Clin. Med. Res., March 1, 2006; 4(1): 53 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Kota, C. V. Ramana, F. A. Tenorio, R. I. Enelow, and J. C. Rutledge Differential Effects of Lipoprotein Lipase on Tumor Necrosis Factor-{alpha} and Interferon-{gamma}-mediated Gene Expression in Human Endothelial Cells J. Biol. Chem., September 2, 2005; 280(35): 31076 - 31084. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Sarzi-Puttini, F Atzeni, A Doria, L Iaccarino, and M Turiel Tumor necrosis factor-a, biologic agents and cardiovascular risk Lupus, September 1, 2005; 14(9): 780 - 784. [Abstract] [PDF]
|
|
|
|
|
|
J. He, S. Yang, and L. Zhang Effects of Cocaine on Nitric Oxide Production in Bovine Coronary Artery Endothelial Cells J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 980 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Heitzer, S. Baldus, Y. von Kodolitsch, V. Rudolph, and T. Meinertz Systemic Endothelial Dysfunction as an Early Predictor of Adverse Outcome in Heart Failure Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1174 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Katz, K. Hryniewicz, I. Hriljac, K. Balidemaj, C. Dimayuga, A. Hudaihed, and A. Yasskiy Vascular Endothelial Dysfunction and Mortality Risk in Patients With Chronic Heart Failure Circulation, January 25, 2005; 111(3): 310 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bachetti, L. Comini, E. Pasini, and R. Ferrari Anti-cytokine therapy in chronic heart failure: new approaches and unmet promises Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F16 - F21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Agnoletti, S. Curello, F. Malacarne, P. Airò, A. Cargnoni, M. Valgimigli, and R. Ferrari Immune activation in severe heart failure: Does etiology play a role? Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F22 - F29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Valgimigli, G. M. Rigolin, A. Fucili, M. D. Porta, O. Soukhomovskaia, P. Malagutti, A. M. Bugli, L. Z. Bragotti, G. Francolini, E. Mauro, et al. CD34+ and Endothelial Progenitor Cells in Patients With Various Degrees of Congestive Heart Failure Circulation, September 7, 2004; 110(10): 1209 - 1212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Rossig, S. Fichtlscherer, C. Heeschen, J. Berger, S. Dimmeler, and A. M. Zeiher The pro-apoptotic serum activity is an independent mortality predictor of patients with heart failure Eur. Heart J., September 2, 2004; 25(18): 1620 - 1625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liao, M. Asakura, S. Takashima, A. Ogai, Y. Asano, Y. Shintani, T. Minamino, H. Asanuma, S. Sanada, J. Kim, et al. Celiprolol, A Vasodilatory {beta}-Blocker, Inhibits Pressure Overload-Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide-Dependent Mechanisms in Mice Circulation, August 10, 2004; 110(6): 692 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. I. Anderson, D. Rahmutula, and D. G. Gardner Tumor Necrosis Factor-{alpha} Inhibits Endothelial Nitric-oxide Synthase Gene Promoter Activity in Bovine Aortic Endothelial Cells J. Biol. Chem., January 9, 2004; 279(2): 963 - 969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoue, T. Zama, T. Kamimoto, R. Aoki, Y. Ikeda, H. Kimura, and M. Hagiwara TNF{alpha}-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells Genes Cells, January 1, 2004; 9(1): 59 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schulz, S. Aker, S. Belosjorow, I. Konietzka, U. Rauen, and G. Heusch Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2084 - H2090. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Aker, S. Belosjorow, I. Konietzka, A. Duschin, C. Martin, G. Heusch, and R. Schulz Serum but not myocardial TNF-{alpha} concentration is increased in pacing-induced heart failure in rabbits Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R463 - R469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Jones, J. J. M. Greer, R. van Haperen, D. J. Duncker, R. de Crom, and D. J. Lefer Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice PNAS, April 15, 2003; 100(8): 4891 - 4896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-Y. Chong, A.D. Blann, and G.Y.H. Lip Assessment of endothelial damage and dysfunction: observations in relation to heart failure QJM, April 1, 2003; 96(4): 253 - 267. [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Malave, A. A. Taylor, J. Nattama, A. Deswal, and D. L. Mann Circulating Levels of Tumor Necrosis Factor Correlate With Indexes of Depressed Heart Rate Variability: A Study in Patients With Mild-to-Moderate Heart Failure Chest, March 1, 2003; 123(3): 716 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Valgimigli, L. Agnoletti, S. Curello, L. Comini, G. Francolini, F. Mastrorilli, E. Merli, R. Pirani, G. Guardigli, P. G. Grigolato, et al. Serum From Patients With Acute Coronary Syndromes Displays a Proapoptotic Effect on Human Endothelial Cells: A Possible Link to Pan-Coronary Syndromes Circulation, January 21, 2003; 107(2): 264 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ferrari Physical training in chronic heart failure: much more than training Eur. Heart J., December 1, 2002; 23(23): 1803 - 1804. [Full Text] [PDF]
|
|
|
|
|
|
V.M. Conraads, P. Beckers, J. Bosmans, L.S. De Clerck, W.J. Stevens, C.J. Vrints, and D.L. Brutsaert Combined endurance/resistance training reduces plasma TNF-{alpha} receptor levels in patients with chronic heart failure and coronary artery disease Eur. Heart J., December 1, 2002; 23(23): 1854 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Schillinger, H. Schneider, K. Minami, R. Ferrari, and G. Hasenfuss Importance of sympathetic activation for the expression of Na+-Ca2+ exchanger in end-stage failing human myocardium Eur. Heart J., July 2, 2002; 23(14): 1118 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kihara, S. Biro, M. Imamura, S. Yoshifuku, K. Takasaki, Y. Ikeda, Y. Otuji, S. Minagoe, Y. Toyama, and C. Tei Repeated sauna treatment improves vascular endothelial and cardiac function in patients with chronic heart failure J. Am. Coll. Cardiol., March 6, 2002; 39(5): 754 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Mitchell, J.-C. Tardif, J. M. O. Arnold, G. Marchiori, T. X. O'Brien, M. E. Dunlap, and M. A. Pfeffer Pulsatile Hemodynamics in Congestive Heart Failure Hypertension, December 1, 2001; 38(6): 1433 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rossig, J. Hoffmann, B. Hugel, Z. Mallat, A. Haase, J.-M. Freyssinet, A. Tedgui, A. Aicher, A. M. Zeiher, and S. Dimmeler Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure Circulation, October 30, 2001; 104(18): 2182 - 2187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. JAIMES, D. D. CASTILLO, M. S. RUTHERFORD, and L. RAIJ Countervailing Influence of Tumor Necrosis Factor-{{alpha}} and Nitric Oxide in Endotoxemia J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1204 - 1210. [Abstract] [Full Text]
|
|
|
|
|
|
L. Rossig, J. Haendeler, Z. Mallat, B. Hugel, J.-M. Freyssinet, A. Tedgui, S. Dimmeler, and A. M. Zeiher Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2081 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Forte, N. Benjamin, S. D. Katz, T. Khan, G. A. Zeballos, L. Mathew, P. Potharlanka, M. Knecht, and J. Whelan Nitric Oxide Synthesis and Congestive Heart Failure Response Circulation, August 8, 2000; 102 (6): e37 - e38. [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]
|
|
|
|
|
|
L. Comini, T. Bachetti, A. Corti, and R. Ferrari A reply Eur. Heart J., May 2, 2000; 21(10): 857 - 857. [PDF]
|
|
|
|
|
|
S. Bulotta, R. Barsacchi, D. Rotiroti, N. Borgese, and E. Clementi Activation of the Endothelial Nitric-oxide Synthase by Tumor Necrosis Factor-alpha . A NOVEL FEEDBACK MECHANISM REGULATING CELL DEATH J. Biol. Chem., February 23, 2001; 276(9): 6529 - 6536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hoffmann, J. Haendeler, A. M. Zeiher, and S. Dimmeler TNFalpha and oxLDL Reduce Protein S-Nitrosylation in Endothelial Cells J. Biol. Chem., October 26, 2001; 276(44): 41383 - 41387. [Abstract] [Full Text] [PDF]
|
|