Relation between the plasma levels of LDL-cholesterol and the expression of the early marker of inflammation long pentraxin PTX3 and the stress response gene p66(ShcA) in pacemaker-implanted patients

Department of Clinical, Morfological and Technological Sciences, Division of Internal Medicine, University Hospital of Trieste, Cattinara, Strada di Fiume 447, I-34149, Trieste, Italy.
Clinical and Experimental Medicine (Impact Factor: 2.96). 04/2007; 7(1):16-23. DOI: 10.1007/s10238-007-0118-y
Source: PubMed


Our goal was to set up a pilot study to explore the possible relation between the expression of p66((ShcA)) and PTX3, two emerging regulators of stress response and inflammation processes, respectively, and the circulating levels of LDL-cholesterol (LDL), a factor implicated in the development of inflammation and oxidative-stress associated diseases such as atherosclerosis. p66((ShcA)) and PTX3 mRNA contents were determined locally, in subcutaneous adipose specimens of non-diabetic pacemaker-implanted patients, and systemically in the circulating white blood cells (WBC) obtained from the same patients. The mean of the circulating LDL levels (125 mg/dl) was chosen as a threshold to identify two groups here considered to have high (>125 mg/dl) and low (<125 mg/dl) LDL plasma levels. Our data show that PTX3 and p66((ShcA)) mRNA levels are significantly more elevated in WBCs and in adipose tissue samples of patients with high levels of LDL compared to those with low levels. Additionally, a multiple regression analysis indicates that among LDL, TG, HDL, total cholesterol, CRP, creatinine and glucose levels, the only variable significantly affecting p66((ShcA)) and PTX3 mRNA expressions either in adipose tissue or in WBCs is represented by the circulating amount of LDL. In conclusion, our results suggest a potential link between the level of LDL and the expression of two genes involved in inflammation/oxidative stress pathways, i.e., p66((ShcA)) and PTX3, thus contributing to further understand the mechanism through which LDL may mediate the pathogenesis of inflammation and oxidative-stress associated diseases such as atherosclerosis.

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    • "Chronic LDL apheresis is extremely effective in reducing the burden of atherosclerosis in FH [32], [21] as a result of modified lipid, proinflammatory and procoagulant profile despite rebounding to pretreatment levels after each session. Serum PTX3 is acutely elevated in critically ill and chronic cardiovascular patients [10], [33] correlating with clinical scores that reflect disease extension and complexity [31], [33]. The current data confirm these observations, as higher PTX3 was observed in subjects with shorter duration of treatment; this inverse relationship was independent from other clinical factors known to influence PTX3 levels, namely age and gender [34]. "
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    ABSTRACT: Background Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, is secreted by vascular cells in response to injury, possibly aiming at tuning arterial activation associated with vascular damage. Severe hypercholesterolemia as in familial hypercholesterolemia (FH) promotes vascular inflammation and atherosclerosis; low-density lipoprotein (LDL) apheresis is currently the treatment of choice to reduce plasma lipids in FH. HELP LDL apheresis affects pro- and antiinflammatory biomarkers, however its effects on PTX3 levels are unknown. We assessed the impact of FH and of LDL removal by HELP apheresis on PTX3. Methods Plasma lipids, PTX3, and CRP were measured in 19 patients with FH undergoing chronic HELP LDL apheresis before and after treatment and in 20 control subjects. In the patients assessment of inflammation and oxidative stress markers included also plasma TNFα, fibrinogen and TBARS. Results At baseline, FH patients had higher (p = 0.0002) plasma PTX3 than matched control subjects. In FH PTX3 correlated positively (p≤0.05) with age, gender and CRP and negatively (p = 0.01) with HELP LDL apheresis vintage. The latter association was confirmed after correction for age, gender and CRP. HELP LDL apheresis acutely reduced (p≤0.04) plasma PTX3, CRP, fibrinogen, TBARS and lipids, but not TNFα. No association was observed between mean decrease in PTX3 and in LDL cholesterol. PTX3 paralleled lipids, oxidative stress and inflammation markers in time-course study. Conclusion FH is associated with increased plasma PTX3, which is acutely reduced by HELP LDL apheresis independently of LDL cholesterol, as reflected by the lack of association between change in PTX3 and in LDL levels. These results, together with the finding of a negative relationship between PTX3 and duration of treatment suggest that HELP LDL apheresis may influence both acutely and chronically cardiovascular outcomes in FH by modulating PTX3.
    PLoS ONE 07/2014; 9(7):e101290. DOI:10.1371/journal.pone.0101290 · 3.23 Impact Factor
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    • "Deletion of p66Shc increases life span in mice, and p66Shc-deficient mice are protected from systemic oxidative stress and atherogenesis induced by high-fat diet [10] [11]. Observations that p66Shc expression is increased in white blood cells and monocytes of patients with coronary artery disease also suggest a possible role for it in human atherosclerotic disease [12]. Despite the well-recognized part for p66Shc in promoting atherosclerosis and vascular dysfunction, its role in platelet biology and thrombosis is not well understood. "
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    ABSTRACT: Background and hypothesis: Hypercholesterolemia leads to a prothrombotic phenotype. Platelet hyperactivity associated with hypercholesterolemia has been attributed, in part, to oxidative stress. P66Shc is a well-known determinant of cellular and organismal oxidative stress. However, its role in platelet biology is not known. We hypothesized that p66Shc mediates platelet hyperactivation and hyperaggregation in hypercholesterolemia. Methods and results: P66Shc was expressed in both human and mouse platelets, as determined by qRT-PCR and immunoblotting. Mouse platelet p66Shc expression was upregulated by hypercholesterolemia induced by high-fat diet feeding. Compared to wild-type mice, high-fat diet-induced p66Shc expression in platelets was suppressed in transgenic mice expressing a short hairpin RNA targeting p66Shc (p66ShcRNAi). High-fat diet feeding of wild-type mice amplified surface P-selectin expression on platelets stimulated by the thrombin receptor agonist protease-activated receptor-4 (PAR4), and increased aggregation of platelets induced by thrombin. These exaggerated platelet responses induced by high-fat diet feeding were significantly blunted in p66ShcRNAi mice. Finally, thrombin-stimulated platelet reactive oxygen species were suppressed in p66ShcRNAi mice. Conclusions: Hypercholesterolemia stimulates p66Shc expression in platelets, promoting platelet oxidative stress, hyperreactivity and hyperaggregation via p66Shc.
    Biochemical and Biophysical Research Communications 05/2014; 449(4). DOI:10.1016/j.bbrc.2014.05.029 · 2.30 Impact Factor
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    Global Telecommunications Conference, 1996. GLOBECOM '96. 'Communications: The Key to Global Prosperity; 12/1996
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