IL-1β Down-Regulates Tissue-Type Plasminogen Activator by Up-Regulating Low-Density Lipoprotein Receptor-Related Protein in AML 12 Cells

Abstract The low-density lipoprotein receptor–related protein (LRP) is a member of the LDL receptor gene family that binds several ligands, including tissue-type plasminogen activator (tPA). tPA is found in blood, where its primary function is as a thrombolytic enzyme, and in the central nervous system where it mediates events associated with cell death. Cerebral ischemia induces changes in the neurovascular unit (NVU) that result in brain edema. We investigated whether the interaction between tPA and LRP plays a role in the regulation of the permeability of the NVU during cerebral ischemia. We found that the ischemic insult induces shedding of LRP's ectodomain from perivascular astrocytes into the basement membrane. This event associates with the detachment of astrocytic end-feet processes and the formation of areas of perivascular edema. The shedding of LRP's ectodomain is significantly decreased in tPA deficient (tPA−/−) mice, is increased by incubation with tPA, and is inhibited by the receptor-associated protein (RAP). Furthermore, treatment with either RAP or anti-LRP IgG results in a faster recovery of motor activity and protection of the integrity of the NVU following middle cerebral artery occlusion (MCAO). Together, these results implicate tPA/LRP interactions as key regulators of the integrity of the NVU.

Download Full-text

Tissue-type plasminogen activator and the low-density lipoprotein receptor–related protein induce Akt phosphorylation in the ischemic brain

Blood ◽

10.1182/blood-2008-02-141630 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2787-2794 ◽

Cited By ~ 43

Author(s):

Jie An ◽

Chen Zhang ◽

Rohini Polavarapu ◽

Xiaohui Zhang ◽

Xiumei Zhang ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Tissue Type ◽

Lipoprotein Receptor ◽

Related Protein ◽

Tissue Type Plasminogen Activator ◽

Akt Phosphorylation ◽

Type Plasminogen Activator ◽

Density Lipoprotein Receptor ◽

Lipoprotein Receptor Related Protein

Abstract Tissue-type plasminogen activator (tPA) is found in the intravascular space and in the central nervous system. The low-density lipoprotein receptor–related protein (LRP) is expressed in neurons and in perivascular astrocytes. During cerebral ischemia, tPA induces the shedding of LRP's extracellular domain from perivascular astrocytes, and this is followed by the development of cerebral edema. Protein kinase B (Akt) is a serine/threonine kinase that plays a critical role not only in cell survival but also in the regulation of the permeability of the blood-brain barrier. We found that, in the early phases of the ischemic insult, the interaction between tPA and LRP induces Akt phosphorylation (pAkt) in perivascular astrocytes and inhibits pAkt in neurons. Coimmunoprecipitation studies indicate that pAkt and LRP's intracellular domain interact in perivascular astrocytes and that this interaction is dependent on the presence of tPA and results in the development of edema. Together, these results indicate that, in the early stages of cerebral ischemia, the interaction between tPA and LRP in perivascular astrocytes induces the activation of a cell signaling event mediated by pAkt that leads to increase in the permeability of the blood-brain barrier.

Download Full-text