Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, and are a cause of major cardiovascular morbidity and mortality. Individuals with APLA-associated thrombosis are treated with lifelong anticoagulation. The primary antigen for APLA is not phospholipid, but ?2-glycoprotein I (?2GPI), an abundant phospholipid-binding glycoprotein. The prothrombotic state associated with anti-?2GPI antibodies may result from their ability to activate vascular endothelial cells (EC) in a ?2GPI-dependent manner. We have demonstrated that activation of EC by APLA is regulated by Krppel-like transcription factors (KLFs), particularly KLF2 and 4. The goal of this application i to define the mechanisms by which EC KLFs regulate the prothrombotic response to APLA. To accomplish this, we will use novel animal models in which the expression of KLFs has been altered in a global or cell-specific manner.
In Specific Aim 1, we will assess the ability of APLA to induce activation of EC isolated from mice lacking KLF2 and/or KLF4, and determine how KLF2/4 affect the endothelial transcriptome in response to APLA. These studies will be coupled to assessment of the ability of KLF2/4 to modulate APLA-mediated arterial, arteriolar, and venular thrombosis in mice.
In Specific Aim 2, we will determine whether the ability of statins to block APLA-mediated EC activation are KLF- dependent. The effects of statins on the transcriptome of APLA-activated EC will also be compared to that observed in the absence of statins. Finally, APLA activate EC through a TLR4-NF?B pathway, and we have demonstrated that the ability of KLF2/4 to block EC activation by APLA reflects sequestration of the NF?B coactivator CBP/p300;however, the role of other transcriptional co-activators and co-repressors of NF?B is unknown.
In Specific Aim 3, we will assess the effects of APLA on assembly of the NF?B transcriptional complex, including co-activators (p300/PCAF) and co-repressors (NCoR/SMRT/HDACs);we will also determine whether statins inhibit assembly of this complex in a KLF-dependent manner. These studies will provide definitive information on the regulation of APLA-induced EC activation and thrombosis by KLFs, and provide insight into targeted interventions to prevent the devastating consequences of APS.
Antiphospholipid antibodies (APLA) are an important cause of venous and arterial thrombosis, leading to significant morbidity and mortality. Activation of endothelial cells (EC) is an important mechanism underlying the ability of APLA to cause thrombosis. This application will assess the role of EC Krppel-like factors (KLF) in regulating EC activation by APLA, and the ability of statin drugs to increase KLF levels and block APLA-induced EC activation and thrombosis.
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