C1qMediated Endothelial Cell Responses Role of C1q and HK

Interaction of C1q with endothelial cells induces a plethora of biological functions including adhesion and spreading; stimulation and expression of the adhesion molecules E-selectin, ICAM-1, and VCAM-1; and production of interleukin (IL)-6, IL-8, and monocyte chemoattrac-tant protein-1 (MCP-1). Endothelial cell adhesion and spreading can be inhibited by both anti-cC1q-R/CR and gC1q-R antibodies, and production of IL-6, IL-8, and MCP-1 can be inhibited by anti cC1q-R/CR. Therefore, at sites of atherosclerotic and inflammatory and vascular lesions, where C1q is present in demonstrable quantities, C1q can trigger or contribute to the inflammatory process not only by activation of the classical pathway of complement, but also by interaction with its receptors, which induces the release of proinflammatory cytokines and recruits inflammatory cells.

In addition to its participation in C1q-mediated responses, gC1q-R, together with urokinase plasminogen activator receptor (uPAR) and cytokeratin-1, has been shown to serve as a high-affinity receptor for HK and FXII as shown by inhibition with monoclonal antibodies to gC1q-R. The binding of HK to gC1q-R is entirely dependent on the presence of 10- to 50-|mM zinc. This is largely because zinc can induce exposure of hydrophobic sites in the C-terminal domain of gC1q-R, which includes those residues recognized by inhibitory monoclonal antibody. It is under these conditions that the binding of HK to the endothelial cell gC1q-R becomes greatly increased. This high-affinity interaction can then facilitate the assembly of proteins of the intrinsic coagulation/kinin-forming cascade resulting in the generation of bradykinin. Bradykinin, a potent vasoactive peptide, can in turn bind to the endothelial cell bradykinin receptor (B2) and induce a wide range of pathophysiologic responses including morphologic changes in the endothe-lium rendering the subendothelial matrix accessible to blood components inflammatory cells. Furthermore, bradykinin can participate in the processes of tumor metastasis and angiogenesis.

Therefore, at sites of atherosclerotic and inflammatory and vascular lesions, where gC1q-R is ubiquitously expressed and both C1q and HK are present (see Figure 1), these molecules can have an additive effect in augmenting the inflammatory process—C1q by activation of complement, and via gC1q-R or other C1q binding proteins,

Figure 1 Immunohistochemical staining of serial sections of the necrotic core of an atherosclerotic lesion of human coronary artery stained with anti-gC1q-R mAb 60.11 (rightpanel) or with isotype- and species-matched antibody (MOPC-21). Upon closer microscopic examination, foam cells in necrotic areas in the deeper intima and the vessel walls in the adventitia showed the strongest gC1q-R staining. Moreover, the necrotic center of calcified atherosclerotic plaques stained strongly for gC1q-R. Staining of endothelial cells was also noted. (see color insert)

Figure 1 Immunohistochemical staining of serial sections of the necrotic core of an atherosclerotic lesion of human coronary artery stained with anti-gC1q-R mAb 60.11 (rightpanel) or with isotype- and species-matched antibody (MOPC-21). Upon closer microscopic examination, foam cells in necrotic areas in the deeper intima and the vessel walls in the adventitia showed the strongest gC1q-R staining. Moreover, the necrotic center of calcified atherosclerotic plaques stained strongly for gC1q-R. Staining of endothelial cells was also noted. (see color insert)

inducing the release of proinflammatory cytokines and the recruitment of inflammatory cells; and HK, by generation of bradykinin, which in turn induces vascular dilation and increased permeability through contraction of endothelial cells and extravascular smooth muscle.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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