0000000000793509
AUTHOR
Markus Baiersdörfer
Chapter 7 Cell Protective Functions of Secretory Clusterin (sCLU)
Secretory clusterin (sCLU) is found as an 80-kDa glycoprotein in virtually all body fluids, in serum it is associated with high-density lipoprotein (HDL). Here, we discuss demonstrated and proposed mechanisms of the cytoprotective functions of sCLU in instances of apoptosis, necrosis, and disease. These include prevention from cell damage by lipid oxidation in blood vessels, removal of dead cell remnants in tissues undergoing various forms of cell death, and clearance of harmful extracellular molecules such as amyloid beta (Aβ) by endocytosis or transcytosis. All these functions may reflect the propensity of sCLU to bind to a wide spectrum of hydrophobic molecules on one hand and to specifi…
Apoptotic Cell Debris and Phosphatidylserine-Containing Lipid Vesicles Induce Apolipoprotein J (Clusterin) Gene Expression in Vital Fibroblasts
The molecular events in cells undergoing programmed cell death (apoptosis) are well studied; however, the response of the surviving neighbor cells to local cell death is largely uncharacterized. Apolipoprotein J (clusterin) is an 80-kDa glycoprotein that has been implied in cytoprotection of the vital cells, presumably by assisting in the clearance of apoptotic vesicles and membrane remnants. Its mRNA is specifically up-regulated in the vital cells of apoptotic tissues. The molecular mechanisms, however, leading to this response are not known. We here show that exposure of vital fibroblasts to apoptotic vesicles, disrupted vital cells, and trypsin-treated membrane remnants induces apoJ mRNA…
Toll-like receptor 3 mediates expression of clusterin/apolipoprotein J in vascular smooth muscle cells stimulated with RNA released from necrotic cells.
Clusterin/Apolipoprotein J is a protein that is upregulated in a broad spectrum of diverse pathological processes. The predominant form is a secreted glycoprotein (sCLU) with cytoprotective and anti-inflammatory properties which shows enhanced expression in vascular smooth muscle cells (VSMC) following aortic injury and in atherosclerotic disease. Recent evidence indicates that during atherosclerosis, Toll-like receptors (TLRs) are activated in vascular cells by endogenous ligands. Here, we analyzed whether CLU expression in VSMC is controlled by TLRs, and stimulated by factors associated with or released by necrotic cells. Activation of TLR3 by the synthetic RNA analogue polyinosinic-polyc…
Statins stimulate the production of a soluble form of the receptor for advanced glycation end products
The beneficial effects of statin therapy in the reduction of cardiovascular pathogenesis, atherosclerosis, and diabetic complications are well known. The receptor for advanced glycation end products (RAGE) plays an important role in the progression of these diseases. In contrast, soluble forms of RAGE act as decoys for RAGE ligands and may prevent the development of RAGE-mediated disorders. Soluble forms of RAGE are either produced by alternative splicing [endogenous secretory RAGE (esRAGE)] or by proteolytic shedding mediated by metalloproteinases [shed RAGE (sRAGE)]. Therefore we analyzed whether statins influence the production of soluble RAGE. Lovastatin treatment of either mouse alveol…