Prolyl-4-hydroxylase-α1 improves the stability of advanced plaques but accelerates the atherosclerotic lesion formation of early plaques

To investigate the changes in Prolyl 4-hydroxylase (P4Hα1) expression during the pathological course of atherosclerotic plaque development and to test the effect of P4Hα1 overexpression on vulnerability of early and advanced plaque in apolipoprotein E-deficient (ApoE^−/−) mice. In vivo, the changes in P4Hα1 level were assessed during the pathological course of spontaneously induced atherosclerotic plaque in the aortic root of ApoE^−/− mice at 10, 12, 14, and 16 weeks of age and fed a high-fat diet. A lentivirus-mediated P4Hα1 construct was transfected in carotid plaque induced in mice by perivascular collar placement for 2 and 10 weeks. After 2 weeks of lenti-P4Hα1 treatment, both early and advanced plaque exhibited stable characteristics, with increased collagen and smooth muscle cell content, reduced macrophage content, and no change in lipid content. Lenti-P4Hα1 treatment of early and advanced plaque substantially increased interstitial collagen content in the fibrous cap of plaque. It increased the carotid plaque size and the relative en face lesion area of the aorta in early but not advanced plaque, with reduced phosphatase and tensin homolog expression. Furthermore, the treatment lowered the expression of inflammatory cytokines and the production and activity of matrix metalloproteinase-9 and -2 in both early and advanced plaque. P4Hα1 overexpression had a differential effect at various stages of plaque pathological progression. P4Hα1 overexpression might be a valuable therapeutic modality in stabilizing advanced but not early plaque because of the adverse event of accelerated lesion formation.