The molecular mechanisms underlying the relationship between low-density lipoprotein (LDL) and the risk of atherosclerosis are not clear. Therefore, detailed information on the protein composition of LDL may help to reveal its role in atherogenesis. Liquid-phase IEF has been used to resolve LDL proteins into well-defined fractions on the basis of pI, which improves the subsequent detection and resolution of low abundance proteins. Besides known LDL-associated proteins, this approach revealed the presence of proteins not previously described to reside in LDL, including prenylcysteine lyase (PCL1), orosomucoid, retinol-binding protein, and paraoxonase-1. PCL1, an enzyme crucial for the degradation of prenylated proteins, generates free cysteine, isoprenoid aldehyde and hydrogen peroxide. Addition of the substrate farnesylcysteine to lipoprotein resulted in a time-dependent generation of H 2 O 2 which was stronger in very low density lipoprotein (VLDL) than in LDL or HDL, reflecting the greater protein content of PCL1 in VLDL. Farnesol, a dead end inhibitor of the PCL1 reaction, reduced H 2 O 2 generation by VLDL. PCL1 is generated along with nascent lipoprotein, as shown by its presence in the lipoprotein secreted by HepG2 cells. The finding that an enzyme associated with atherogenic lipoproteins can itself generate an oxidant suggests that PCL1 may play a significant role in atherogenesis.Abbreviations: FAD, flavin adenine dinucleotide; FC, farnesylcysteine; H 2 O 2 , hydrogen peroxide; HDL, high density lipoprotein; LDL, low density lipoprotein; PCL1, prenylcysteine lyase; RBP, retinol-binding protein; SAA, serum amyloid A; VLDL, very low density lipoprotein * These authors contribute equally to this work.
the inflammatory and proliferative responses triggered by tissue injury. We have previously shown that PAR1 or PAR2 occupancy by specific PAR-agonist peptides (PAR-APs) induces tissue factor (TF) expression in human umbilical vein endothelial cells (HUVECs), where TF regulation by PAR1 (but not by PAR2) requires intact endothelial caveolin-enriched membrane microdomains in which PAR1 and caveolin-1 associate. Objectives: The aim of this study was to determine the effects of cholesterol-lowering agents (statins) and cholesterol-loading lipoprotein on PAR1-AP-mediated and PAR2-AP-mediated TF induction in HUVECs. Results: Statins completely prevented TF induction by PAR-APs in an isoprenoid-independent manner, induced the delocalization of PAR1 from caveolin-enriched membrane microdomains without affecting PAR1 mRNA, and decreased PAR2 mRNA and protein levels. Statins also prevented PAR-AP-mediated extracellular signal-related kinase 1/2 activation, which is crucial for TF induction. The redistribution of PAR1 is accompanied by the relocation of the membrane microdomainassociated G-protein a, caveolin-1, and Src, which we previously showed to play a key role in signal transduction and TF induction. Conversely, cholesterol loading potently amplified PAR1-AP-induced TF, probably as a result of the increased abundance of PAR1 and the Src and G-protein a signaling molecules in the caveolin-1-enriched fraction, without affecting PAR1 mRNA. Conclusions: As PARs have important functions in hemostasis, cancer, thrombosis, and inflammatory processes, our findings that statins prevent TF induction by PAR-APs altering the membrane localization of PAR1 and the expression of PAR2 suggest that they may provide health benefits other than reducing atherosclerosis.
Introduction Valve-in-Valve transcatheter aortic valve implantation (ViV-TAVI) is an appealing treatment option for patients with degenerated aortic bioprosthetic valves. However, high post-procedural transprosthetic gradients are very common after ViV-TAVI than after TAVI for native-valve aortic stenosis. Aim We sought to evaluate transprosthetic gradients (ΔP) and hemodynamic outcome in patients undergoing ViV-TAVI according to valve type and balloon post-dilation (balloon-expandable vs self-expandable with and without post-dilation). Material and methods We retrospectively analyzed 111 patients undergoing ViV-TAVI. A balloon-expandable valve was used in 35 patients (32%, Group 1), a self-expandable valve in 76 cases of which 39 (35%, Group 2) without balloon post-dilation and 37 (33%, Group 3) with balloon post-dilation. A comprehensive transthoracic echocardiography (TTE) was performed in all patients at baseline, at discharge and at 6-months follow-up. Results Successful ViV-TAVI was performed in 110 patients (99%). Baseline peak and mean ΔP, left ventricular volumes, ejection fraction, and pulmonary artery systolic pressure were similar among groups. A significant improvement in all echocardiographic parameters was observed in all groups over time (Table 1). In particular, a significant reduction in postprocedural gradients was observed at discharge and at 6-months follow-up compared to baseline in all groups. Immediately after ViV-TAVI procedure, the lowest value of mean ΔP was observed in Group 3 (12±7 mmHg) compared to both Group 1 (20±9 mmHg) and Group 2 (17±8 mmHg, p=0.001). This result was confirmed at 6-months follow-up (p=0.012). Rate of small valve size (≤23 mm) implanted was similar among groups (Group 1: 78%, Group 2: 60%, Group 3: 62%, p=0.123). Similar 1-year all-cause mortality was observed among groups (9%, 13%, 0%, respectively, p=0.135). Conclusions In patients with failed surgical aortic prosthesis, ViV-TAVI is an effective option and is associated with sustained improved hemodynamics in all patients. Anyway, the choice of prosthetic valve type and implantation technique are relevant on residual transprosthetic gradients and should be taken into account for a better long-term outcome. Funding Acknowledgement Type of funding sources: None.
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