Role of NonO–histone interaction in TNFα-suppressed Prolyl-4-hydroxylase α1

Inflammation is a key process in cardiovascular diseases. The extracellular matrix (ECM) of the vasculature is a major target of inflammatory cytokines, and TNFα regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNFα-induced suppression of prolyl-4 hydroxylase alpha1 (P4Hα1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNFα activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNFα response element in the P4Hα1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4Hα1 promoter. Furthermore, we found that TNFα oxidized DJ-1, which may be essential for the NonO–P4Hα1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNFα-induced NonO–P4Hα1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.