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CLINICAL RESEARCH: ACUTE CORONARY SYNDROME

Persistent Activation of Nuclear Factor Kappa-B Signaling Pathway in Patients With Unstable Angina and Elevated Levels of C-Reactive Protein

Evidence for a Direct Proinflammatory Effect of Azide and Lipopolysaccharide-Free C-Reactive Protein on Human Monocytes Via Nuclear Factor Kappa-B Activation

Giovanna Liuzzo, MD, PhD^_*,_*, Matteo Santamaria, MD^_*, Luigi M. Biasucci, MD, FACC^_*, Michela Narducci, PhD^_*, Valeria Colafrancesco, PhD^_*, Annalisa Porto, PhD, Salvatore Brugaletta, MD^_*, Michela Pinnelli, MD^_*, Vittoria Rizzello, MD^_*, Attilio Maseri, MD, FACC and Filippo Crea, MD, FACC^_*

^_* Institute of Cardiology, Catholic University, Rome, Italy
Dipartimento Cardiotoracovascolare, Universitá "Vita e Salute," Milan, Italy.

Manuscript received March 29, 2006; revised manuscript received July 10, 2006, accepted July 17, 2006.

^_* Reprint requests and correspondence: Dr. Giovanna Liuzzo, Institute of Cardiology, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy. (Email: gliuzzo{at}hotmail.com).

OBJECTIVES: Our study investigated: 1) the contribution of nuclear factor kappa-B (NF-B) signaling pathway to the enhanced inflammatory response observed in unstable angina (UA) patients with elevated levels of C-reactive protein (CRP); and 2) whether CRP may have direct proinflammatory effects via NF-B activation.

BACKGROUND: Unstable angina patients with elevated CRP have enhanced inflammatory response and increased risk of persistent instability, myocardial infarction, and death.

METHODS: We studied 28 patients with history of UA and persistently elevated CRP (>3 mg/l) followed for 24 months and free of symptoms for at least 6 months (group 1), 14 patients with history of UA and low CRP (group 2), and 24 patients with chronic stable angina and low CRP (group 3). Peripheral blood monocytes were analyzed for spontaneous NF-B activation and interleukin (IL)-6 and tumor necrosis factor (TNF)- production. To assess the direct proinflammatory effects of CRP, monocytes from 8 healthy subjects were stimulated in vitro with increasing doses of CRP (5 to 10 to 25 µg/ml), lipopolysaccharide (LPS) (1 to 10 ng/ml), or both.

RESULTS: Spontaneous NF-B activation in vivo was demonstrated in 82% of group 1 versus 14% of group 2 and 21% of group 3 patients (p < 0.001). Interleukin-6 and TNF- production was significantly correlated with the NF-B activation status (r = 0.55, p < 0.001 and r = 0.53, p = 0.006, respectively). Patients with NF-B activation had recurrence of acute coronary events (60% vs. 28%; p = 0.017). C-reactive protein induced a significant but modest in vitro NF-B activation in human monocytes (p = 0.002). Coincubation with LPS produced a greater-than-additive response (p < 0.01 vs. CRP and LPS alone).

CONCLUSIONS: Nuclear factor kappa-B activation might represent a mechanism by which CRP amplifies and perpetuates the inflammatory component of acute coronary syndromes and influences the clinical outcome.

Abbreviations and Acronyms   ACS = acute coronary syndromes   CRP = C-reactive protein   IL = interleukin   LPS = lipopolysaccharide   NF-B = nuclear factor kappa-B   TNF = tumor necrosis factor   UA = unstable angina

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