Dysfunctional High-Density Lipoprotein and the Potential of Apolipoprotein A-1 Mimetic Peptides to Normalize the Composition and Function of Lipoproteins

Imaizumi, Satoshi; Navab, Mohamad; Morgantini, Cecilia; Charles‐Schoeman, Christina; Su, Feng; Gao, Feng; Kwon, Murray; Ganapathy, Ekambaram; Meriwether, David; Farias‐Eisner, Robin; Fogelman, Alan M.; Reddy, Srinivasa T.

doi:10.1253/circj.cj-11-0460

Cited by 37 publications

(31 citation statements)

References 55 publications

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“…These examples reflect the very heterogeneous nature of HDL which makes HDL genetics very complex [45]. Although high-density lipoprotein-cholesterol levels in large epidemiological studies are inversely related to the risk of coronary heart disease (CHD), increasing the level of circulating HDL does not necessarily decrease the risk of CHD events, CHD deaths, or mortality [46]. Typically, total plasma HDL contains 20% -30% (wt/wt) phospholipids, 3% -5% free cholesterol, 14% -18% cholesteryl ester and 3% -6 % triglycerides.…”

Section: Discussionmentioning

confidence: 99%

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia

Yeğin¹,

Ay²,

Aydın³

et al. 2012

IJCM

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Background: Several lines of evidence, including postmortem studies, suggest increased oxidative stress and inflammation in patients with schizophrenia. Alteration of oxidative stress markers has been reported in schizoprenia studies, but with inconsistent results. Oxidized low-density lipoproteins (oxLDL) have been reported to be capable of eliciting neurocytotoxicity. On the other hand, paraoxonase (PON1), an arylesterase(ARE), plays a role in protection against oxidative modifications of LDL and is considered to be one of the antioxidant enzymes. There are no studies showing the changes in oxidative stress and inflammation together, nor the activities of PON1 and ARE in schizophrenic patients. In this study, we examined PON1, ARE activities and oxidative/anti-oxidative markers in patients with chronic schizophrenia and healthy controls. Methods: We recruited 30 male chronic schizophrenic patients and 30 male healthy control subjects and examined C-reactive protein(CRP), fibrinogen, PON1, ARE and plasma total antioxidant status (TAS) and total oxidant status (TOS), oxidative stress index(OSI) in both groups. Schizophrenia symptoms were assessed using the positive and negative syndrome scale (PANSS). The related routine lipid profile parameters including HDL were also examined. Results: Patients had significantly higher CRP, fibrinogen, TOS and OSI levels; but the patients and control subjects did not differ on activities of the antioxidant enzymes PON1 and ARE. Interestingly, there were not any group differences in the lipid profile parameters except the triglyceride levels, that increased significantly in the patient group. Conclusions: In the present study, reporting the ARE activities besides the PON1 activities in schizophrenic patients for the first time, we showed that PON1 and ARE enzyme activities were not statistically different in patients with chronic schizophrenia. This study provides additional evidence of increased oxidative stress and inflammation in chronic schizophrenia, but no alterations in the antioxidant status were observed. Our results suggest that other mechanisms than the high density lipoprotein(HDL)-disfunctionality, namely decreases in PON1 or ARE enzyme activities, are more important in oxidative or antioxidative pathophysiological processes in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia

Yeğin¹,

Ay²,

Aydın³

et al. 2012

IJCM

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“…[10][11][12] To counteract this inflammatory milieu, plasma apolipoprotein A-I (apoA-I), the principal apolipoprotein constituent of HDL, normally confers "anti-inflammatory" activity on HDL. However, "pathologic HDL" can occur during "chronic, acute phase responses" that are paradoxically "proinflammatory," 13,14 while inflammation may be regulated by complexes of hemoglobin-haptoglobin. 15 Overexpression of apoA-I (which contains 243 amino acid residues) has been shown to ameliorate atherosclerosis in experimental animals.…”

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confidence: 99%

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

et al. 2015

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Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for highdensity lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.Keywords: pulmonary arterial hypertension, low-density lipoprotein, high-density lipoprotein, inflammatory index, hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, pulmonary arterial endothelial cells, pulmonary arterial smooth muscle cells.

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“…Another apoA-I mimetic peptide, 4F, removes plasma oxidized lipids (PLs and fatty acids) and improves the antiinflammatory properties of HDL. 102 …”

Section: Hdl-c-raising and Atheroprotective Effects Of Exercisementioning

confidence: 99%

Therapeutic Approaches to the Regulation of Metabolism of High-Density Lipoprotein

Zhang

Kawachi

Miura

et al. 2013

Circ J

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Dysfunctional High-Density Lipoprotein and the Potential of Apolipoprotein A-1 Mimetic Peptides to Normalize the Composition and Function of Lipoproteins

Cited by 37 publications

References 55 publications

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

Therapeutic Approaches to the Regulation of Metabolism of High-Density Lipoprotein

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