LAUSR

Platelets stored at 4oC exhibit equivalent or superior hemostatic function compared to 22oC platelets (PLTs), but have shorter circulation times and a decreased ability to modulate vascular permeability. These differences may be due to morphological changes and storage induced activation. Using a proteomics-based approach, we found that 4oC stored PLTs express decreased α-tubulin, a key PLT structural protein. PLT activation is characterized by α-tubulin de-acetylation, which is regulated by histone deacetylase-6 (HDAC-6). We hypothesized that inhibition of HDAC-6 in stored PLTs will improve their ability to regulate vascular permeability through reduced activation and α-tubulin deacetylation. In an in vivo model of vascular permeability, treatment of 4oC PLTs with the HDAC-6 inhibitor, tubacin, enhanced the vasculo-protective properties of untreated 4oC PLTs. 4oC PLT circulation, however, was unchanged by tubacin treatment, suggesting that circulation time may not be a critical factor in determining the vasculo-protective effects of PLTs. Assessing the factor content of stored PLTs revealed that angiopoietin-1 (Ang-1) increased in 4oC PLTs over time, which was further enhanced by tubacin treatment. In addition, angiopoietin-2 (Ang-2), an inducer of vascular leak and antagonist of Ang-1, inhibited PLT barrier protection, suggesting involvement of the Tie-2 pathway. This study demonstrates that HDAC-6 inhibition with tubacin attenuates the diminished vasculo-protective properties of 4oC PLTs, and these properties may be independent of PLT circulation time.