Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis

Speidl, Walter S.; Exner, Markus; Amighi, Jasmin; Kastl, Stefan P.; Zorn, Gerlinde; Maurer, Gerald; Wagner, Oswald; Huber, Kurt; Minar, Erich; Wojta, Johann; Schillinger, Martin

doi:10.1093/eurheartj/ehi339

Cited by 130 publications

(112 citation statements)

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“…The extent of C5b-9 deposition appears to correlate with the severity of the lesion [49], with the greatest deposition of iC3b reported in vulnerable and ruptured plaques [49,50]. Indeed, elevations in circulating C5a levels have been associated with increased cardiovascular risk in patients with advanced atherosclerosis [51]. Results from the present study suggest that PMP can transport complement components to sites of vascular injury, and support local inflammation by supporting classical pathway complement activation.…”

Section: Discussionmentioning

confidence: 55%

Expression of complement components and inhibitors on platelet microparticles

2008

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Platelet microparticles (PMP) are released from activated platelets and play an important role in hemostasis, thrombosis and inflammation. Since platelets were recently found to demonstrate an intrinsic capacity for activating both classical and alternative pathways of the complement system, the present study extended these observations to PMP. PMP were generated by treating platelets with 10 µM A23187 (37°C, 5 min). PMP were identified by flow cytometry, based on size, Annexin V binding, and expression of P-selectin and GPIIb (CD41). PMP expressed gC1qR/p33, a multifunctional cellular protein that was recently described to activate the classical complement cascade. PMP also expressed the classical pathway and contact system regulator, CI inhibitor (C1-INH), as well as CD55 and CD59. Despite C1-INH expression, PMP supported classical pathway C4 activation in the presence of purified C1 and C4. Moreover, statistically significant deposition of C3b and C5b-9 was detected on PMP exposed to plasma, concurrently with expression of CD55 and CD59. These data provide the first evidence for the ability of PMP to support in situ complement activation. Complement activation contributes to a variety of vascular and inflammatory disease states including atherosclerosis and ischemia/reperfusion injury.

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Section: Discussionmentioning

confidence: 55%

Expression of complement components and inhibitors on platelet microparticles

2008

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“…Thus, complement activation can contribute directly to local tissue destruction, inflammation, and atherogenesis. In this regard, Speidl et al (Speidl, Exner et al 2005) recently reported that plasma C5a levels were predictive of cardiovascular risk in patients with advanced atherosclerosis.…”

Section: Discussionmentioning

confidence: 98%

Classical pathway complement activation on human endothelial cells

Ghebrehiwet

Weksler

Peerschke

2007

Molecular Immunology

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Endothelial cells regulate vascular integrity and express complement binding proteins including gC1qR/p33 (gC1qR), which recognize C1q, a subunit of the first component of the classical complement pathway. Experiments were performed to investigate classical complement pathway activation on resting endothelial cells and endothelial cells exposed to shear stress. C1q deposition and C4 activation (C4d) were demonstrated by solid phase ELISA and flow cytometry on human microvascular and umbilical vein endothelial cells after exposure to serum or plasma. C4d deposition was accompanied by downstream complement activation including C3b and C5b-9 deposition. C4 activation failed to occur in C1q depleted serum, but was not affected by Factor B depleted serum, confirming classical complement pathway activation. Moreover, C4 activation occurred following exposure of endothelial cells to purified C1 and C4, in the absence of other plasma proteins, and in the absence of detectable cell surface IgG and IgM. Shear stress (18 dynes/cm 2 ) increased C1q (n=9, p<0.05) and C4d (n=9, p<0.05) deposition approximately 2-fold, and enhanced endothelial cell gC1qR expression (n=7, p<0.05). Treatment of endothelial cells with anti gC1qR monoclonal antibody F(ab') 2 fragments reduced C4d deposition by approximately 20% (n=5, p<0.05). These data demonstrate direct classical complement pathway activation on endothelial cells. gC1qR appears to play a minor but definable role, whereas cell surface IgG or IgM are not required.

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“…Moreover, iC3b deposition appears to be highest in vulnerable and ruptured plaques (Laine, Pentikainen, Wurzner, Penttila, Paavonen, Meri, and Kovanen 2002). Moreover, elevations in circulating C5a have been associated with increased cardiovascular risk in patients with advanced atherosclerosis (Seidl, Exner, Amighi, Kastl, Zorn, Maurer, Wagner, Huber, Minar, Wojta, and Schillinger 2005).…”

Section: Pathophysiology Of Platelet Mediated Complement Activationmentioning

confidence: 99%