Pulmonary Hypertension: Old Targets Revisited (Statins, PPARs, Beta-Blockers)

Watson, Geoffrey; Oliver, Eduardo; Zhao, Lan; Wilkins, Martin R.

doi:10.1007/978-3-642-38664-0_21

Cited by 4 publications

(1 citation statement)

References 83 publications

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“…[24][25][26][27][28] Further, in studies of pleiotropic HMG CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase inhibitor medications ("statins") which, despite effectuating a reduction in "oxidant stress," a reduction in Rho/Rho-kinase (ROCK) signaling, enhanced endothelial nitric oxide production, and increased expression of bone morphogenetic protein receptor type 2, have been disappointing in both the treatment of PAH and experimental models of vascular PGI 2 production. [29][30][31][32][33][34] "Oxidant stress" has been reported in PAH by Cracowski et al, 35 who described increased isoprostane urinary levels that correlated with worsened patient survival. Further, using oligonucleotide microarray gene expression, Geraci et al 36 have described an increase in pulmonary expression of oxidative genes in PAH patients.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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Are statins beneficial for the treatment of pulmonary hypertension?

Wang

Yang

Wang

2017

Chronic Diseases and Translational Medicine

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Pulmonary hypertension (PH) is a condition characterized by vasoconstriction and vascular remodeling with a poor prognosis. The current medical treatments available are supportive care therapy and pulmonary vascular-targeted therapy. Targeted treatments for PH include prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors; however, these treatments cannot reverse pulmonary vascular remodeling. Recently, many novel treatment options involving drugs such as statins have been emerging. In this review, we attempt to summarize the current knowledge of the role of statins in PH treatment and their potential clinical effects. Many basic researches have proved that statins can be helpful for the treatment of PH both in vitro and in experimental models. The main mechanisms underlying the effects of statins are restoration of endothelial function, attenuation of pulmonary vascular remodeling, regulation of gene expression, regulation of intracellular signaling processes involved in PH, anti-inflammatory responses, and synergy with other targeted drugs. Nevertheless, clinical researches, especially randomized controlled trials for PH are rare. The current clinical researches show contrasting results on the clinical effects of statins in patients with PH. Carefully designed randomized, controlled trials are needed to test the safety and efficacy of statins for PH treatment.

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The perspectives of application of statins under pulmonary hypertension

Baksheev¹,

Kolomoetz²,

Shklovskiy³

et al. 2016

Medical Journal of the Russian Federation

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The present publications' review considers perspectives of application of statins under pulmonary hypertension. Nowadays, there are quite encouraging experimental data concerning positive versatile effect of statins on lesser blood circulation. The results of study of this issue with participation of patients are singular and continue to be controversial still. The clinical substantiation of application of new pharmaceuticals effecting molecular mechanisms of pathogenesis of pulmonary hypertension (re-modeling, endothelial dysfunction, function of right ventricle) requires carrying out of large investigations placebo-controlled by design and statistical processing. Precisely in this context the application of statins is of interest as potentially strategic direction in treatment of pulmonary hypertension.

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Pulmonary Hypertension: Old Targets Revisited (Statins, PPARs, Beta-Blockers)

Cited by 4 publications

References 83 publications

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

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

Are statins beneficial for the treatment of pulmonary hypertension?

The perspectives of application of statins under pulmonary hypertension

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