The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development

Abstract

ObjectiveGenetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)-mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia.Methods and resultsPCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes.To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals.ConclusionsThese results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…Intimal hyperplasia is based on vascular inflammation and NF‐ k B activation and the HAT PCAF promoted NF‐ κ B‐regulated inflammation. Garcinol suppressed CCL2 and TNF‐ α expression in leukocytes and vascular smooth muscle cells and reduced arterial adherence and infiltration by leukocytes and macrophages in vivo when administered in a Pluronic gel enabling a slow garcinol drug release . In contrast to these and other previous findings about the considerable anti‐inflammatory activities of garcinol, a newer study described the enhancement of lipopolysaccharide(LPS)‐induced inflammation by intraperitoneally administered garcinol (injection of 10 mg/kg in DMSO) both in vitro and in vivo .…”

“…Suppression of leukocyte and vascular smooth muscle cell inflammation process in vitro, reduced arterial adherence and infiltration by leukocytes and macrophages in vivo …”

“…Skin inflammation Inhibition of 12-O-tetradecanoylphorbol induced inflammation process and tumorigenesis in vitro and in vivo [65] Suppression of NF-κB, ERK, JNK, p38 MAPK, PI3 K, and Akt [65] Intimal hyperplasia Suppression of leukocyte and vascular smooth muscle cell inflammation process in vitro, reduced arterial adherence and infiltration by leukocytes and macrophages in vivo [66] Suppression of CCL2 and TNF-α [66] LPS-induced inflammation Increase of LPS-induced inflammation process invitro and in vivo [67] Increased expression of TNF-α and IL-6 [67] Collagen-induced arthritis (CIA)…”

“…Decrease of mortality and of seizure scores in vivo [86] Suppression of BDNF and TrkB and upregulation of GABA A and GAD65 [86] Cocaine abuse Support of drug abstinence [87,88] Inhibition of reinstatement by reconsolidationbased modes [85,88] reduced arterial adherence and infiltration by leukocytes and macrophages in vivo when administered in a Pluronic gel enabling a slow garcinol drug release. [66] In contrast to these and other previous findings about the considerable anti-inflammatory activities of garcinol, a newer study described the enhancement of lipopolysaccharide(LPS)-induced inflammation by intraperitoneally administered garcinol (injection of 10 mg/kg in DMSO) both in vitro and in vivo. [6,67] The expression of TNF-α and IL-6 was markedly increased by garcinol in this case, which was correlated with reduced acetylation of NF-κB.…”

P300/CBP‐associated factor regulates transcription and function of isocitrate dehydrogenase 2 during muscle differentiation

“…factors and modulating function of non-nuclear proteins through post-translational addition of acetyl groups (2). Recently, PCAF emerged involved in the onset of neurologic disorders (3), in angiogenesis regulation, and in pathophysiological processes associated with cardiovascular risks, such as inflammation and neointima formation (4,5). Furthermore, several studies pointed out the role of PCAF during skeletal muscle differentiation/ development in association with MyoD (6,7), as well as its ability to acetylate nonhistone proteins, such as p53 (8), microtubule associated proteins (9), and the key regulator of energy metabolism, peroxisome proliferator-activated receptor gamma coactivator-1a (10).…”