Lysine Acetyltransferase PCAF Is a Key Regulator of Arteriogenesis

作者：Bastiaansen Antonius J N M; Ewing Mark M; de Boer Hetty C; Kraan Tineke C van der Pouw; de Vries Margreet R; Peters Erna A B; Welten Sabine M J; Arens Ramon; Moore Scott M; Faber James E; Jukema J Wouter; Hamming Jaap F; Nossent A Yael; Quax Paul H A^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2013, 33(8): 1902-1910.

DOI：10.1161/ATVBAHA.113.301579

• inflammation
• monocytes
• p300-CBP-associated factor
• peripheral arterial disease

Objective %26lt;br%26gt;Therapeutic arteriogenesis, that is, expansive remodeling of preexisting collaterals, using single-action factor therapies has not been as successful as anticipated. Modulation of factors that act as a master switch for relevant gene programs may prove more effective. Transcriptional coactivator p300-CBP-associated factor (PCAF) has histone acetylating activity and promotes transcription of multiple inflammatory genes. Because arteriogenesis is an inflammation-driven process, we hypothesized that PCAF acts as multifactorial regulator of arteriogenesis. %26lt;br%26gt;Approach and Results %26lt;br%26gt;After induction of hindlimb ischemia, blood flow recovery was impaired in both PCAF(-/-) mice and healthy wild-type mice treated with the pharmacological PCAF inhibitor Garcinol, demonstrating an important role for PCAF in arteriogenesis. PCAF deficiency reduced the in vitro inflammatory response in leukocytes and vascular cells involved in arteriogenesis. In vivo gene expression profiling revealed that PCAF deficiency results in differential expression of 3505 genes during arteriogenesis and, more specifically, in impaired induction of multiple proinflammatory genes. Additionally, recruitment from the bone marrow of inflammatory cells, in particular proinflammatory Ly6C(hi) monocytes, was severely impaired in PCAF(-/-) mice. %26lt;br%26gt;Conclusions %26lt;br%26gt;These findings indicate that PCAF acts as master switch in the inflammatory processes required for effective arteriogenesis.

• 出版日期2013-8