Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

Palacios, Roberto; Hernanz, Raquel; Martin, Anastasia; Pérez-Girón, José Vicente; Barrús, María Teresa; González-Carnicero, Zoe; Aguado, Ana M.; Jaisser, Frédéric; Briones, Ana M.; Salaíces, Mercedes; Alonso, María J.

doi:10.1038/s41598-019-52839-6

Cited by 21 publications

(9 citation statements)

References 60 publications

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“…Following the investigation of other inflammatory effects on the BBB caused by TNFα, we found increased expression of Cox-2, VCAM-1 and ICAM-1 and increased secretion of IL-6, IL-8 and MCP1, with pioglitazone being capable of reversing the effects seen for VCAM-1, ICAM-1 and MCP1 only. At first, some of these are seemingly contradicting effects, as pioglitazone was reported in other studies to reduce levels of both interleukins and Cox-2 alongside VCAM-1 and ICAM-1, but these were reported under different conditions in different body compartments [ 36 , 37 , 38 , 39 ]; these results, while being reported on endothelial cells, are still far from the BBB model here used. As there are no studies on the actions of pioglitazone on inflammatory effects on the BBB for the sake of comparison, it is reasonable to assume, under the conditions here employed, that pioglitazone does not modulate inflammation in all of its aspects in the BBB.…”

Section: Discussionmentioning

confidence: 79%

Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

Rocha

Loiola

Paula-Silva

et al. 2022

IJMS

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Biological mediators secreted during peripheral chronic inflammation reach the bloodstream and may damage the blood–brain barrier (BBB), triggering central nervous system (CNS) disorders. Full-fledged human BBB models are efficient tools to investigate pharmacological pathways and mechanisms of injury at the BBB. We here employed a human in vitro BBB model to investigate the effects of either plasma from inflammatory bowel disease (IBD) patients or tumor necrosis factor α (TNFα), a cytokine commonly released in periphery during IBD, and the anti-inflammatory role of pioglitazone, a peroxisome proliferator-activated receptor γ agonist (PPARγ). The BBB model was treated with either 10% plasma from healthy and IBD donors or 5 ng/mL TNFα, following treatment with 10 µM pioglitazone. Patient plasma did not alter BBB parameters, but TNFα levels in plasma from all donors were associated with varying expression of claudin-5, claudin-3 and ICAM-1. TNFα treatment increased BBB permeability, claudin-5 disarrangement, VCAM-1 and ICAM-1 expression, MCP1 secretion and monocyte transmigration. These effects were attenuated by pioglitazone. Plasma from IBD patients, which evoked higher BBB permeability, also increased ICAM-1 expression, this effect being reversed by pioglitazone. Our findings evidence how pioglitazone controls periphery-elicited BBB inflammation and supports its repurposing for prevention/treating of such inflammatory conditions.

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Section: Discussionmentioning

confidence: 79%

Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

Rocha

Loiola

Paula-Silva

et al. 2022

IJMS

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“…In a study that used a hypertensive rat model, pioglitazone was shown to activate peroxisome-activated receptors (PPARs) by regulating endothelin-1 (ET-1) expression to attenuate the effects of oxidative stress on the vasculature. In addition, pioglitazone may improve vasodilatory function by increasing ET-1 receptor B (ETB) expression to release endothelial cell relaxing factors ( 81 ). The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive trial) was the first large RCT to evaluate the effects of pioglitazone monotherapy on cardiovascular outcomes, and the results showed that pioglitazone reduced the risks of all-cause mortality, nonfatal heart attack, and stroke in patients with T2DM with macrovascular disease ( 82 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antidiabetic Drugs on Endothelial Function in Patients With Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis

et al. 2022

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BackgroundThe changes of endothelial function in type 2 diabetes mellitus (T2DM) patients are closely associated with the development of cardiovascular disease (CVD). However, it is still unclear whether commonly used antidiabetic drugs can improve endothelial function. Flow-mediated dilation (FMD) is a noninvasive tool for evaluating endothelial function, which typically examines changes in the brachial artery diameter in response to ischemia using ultrasound. We performed a network meta-analysis (NMA) to explore the associations between changes in endothelial function and antidiabetic drugs by evaluating FMD in T2DM patients.MethodsWe systematically searched several electronic databases for randomized controlled trials (RCTs) published from inception until January 25, 2022 with no language restriction. The primary outcome was FMD change in all studies, and we performed subgroup analysis in T2DM patients without CVD. NMA was performed to calculate the mean differences (MDs) with 95% confidence intervals (CIs).ResultsFrom the 1,987 candidate articles identified in the initial search, 30 RCTs were eventually included in the analysis. In all studies, glucagon-like peptide-1 receptor (GLP-1R) agonists [MD = 3.70 (1.39–5.97)], TZD [MD = 1.96 (0.006–3.89)] produced improvement of FMD change compared to lifestyle intervention. GLP-1R agonists [MD = 3.33 (1.36–5.34) and MD = 3.30 (1.21–5.43)] showed significantly greater improvements in FMD change in pairwise comparisons with sulfonylureas and placebo. SGLT-2i also showed efficacy compared to sulfonylureas (MD = 1.89, 95% CI, 0.10, 3.75). In studies of T2DM patients without CVD, GLP-1R agonists [MD = 3.53 (1.24–5.76)], and TZD [MD = 2.30 (0.27–3.24)] produced improvements in FMD change compared to lifestyle treatment. GLP-1R agonists [MD = 3.25 (1.13–5.40), and MD = 3.85 (1.68–6.13)] showed significantly greater improvements in pairwise comparisons with sulfonylureas, and placebo.ConclusionIn T2DM patients, both GLP-1R agonists, SGLT-2i and TZD have favorable effects to improve endothelial function in T2DM patients. In T2DM patients without CVD, GLP-1R agonists had a greater effect to improve endothelial function than sulfonylureas. These suggested that GLP-1R agonists are associated with significantly improved endothelial function in T2DM patients.

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“…PPARγ not only regulates hypoxia-induced ET-1 levels but also other components of the ET-1 signaling pathway, such as Endothelin-Converting Enzyme 1 (ECE-1) mRNA levels, ETA, and ETB (21). Due to the above, it is believed that PPARγ agonists could reverse pulmonary vascular remodeling (22,23). Furthermore, a malfunction of BMPR2 has been shown to decrease endogenous PPARγ activity and promote metabolic pathways associated with vascular remodeling (24).…”

Section: Discussionmentioning

confidence: 99%

Common Variation in EDN1 Regulatory Regions Highlights the Role of PPARγ as a Key Regulator of Endothelin in vitro

Lago-Docampo

Solarat

Méndez-Martínez

et al. 2022

Front. Cardiovasc. Med.

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Pulmonary Arterial Hypertension (PAH) is a rare disease caused by the obliteration of the pulmonary arterioles, increasing pulmonary vascular resistance and eventually causing right heart failure. Endothelin-1 (EDN1) is a vasoconstrictor peptide whose levels are indicators of disease progression and its pathway is one of the most common targeted by current treatments. We sequenced the EDN1 untranslated regions of a small subset of patients with PAH, predicted the effect in silico, and used a luciferase assay with the different genotypes to analyze its influence on gene expression. Finally, we used siRNAs against the major transcription factors (TFs) predicted for these regions [peroxisome proliferator-activated receptor γ (PPARγ), Krüppel-Like Factor 4 (KLF4), and vitamin D receptor (VDR)] to assess EDN1 expression in cell culture and validate the binding sites. First, we detected a single nucleotide polymorphism (SNP) in the 5' untranslated region (UTR; rs397751713) and another in the 3'regulatory region (rs2859338) that altered luciferase activity in vitro depending on their genotype. We determined in silico that KLF4/PPARγ could bind to the rs397751713 and VDR to rs2859338. By using siRNAs and luciferase assays, we determined that PPARγ binds differentially to rs397751713. PPARγ and VDR Knock-Down (KD) increased the EDN1 mRNA levels and EDN1 production in porcine aortic endothelial cells (PAECs), while PPARγ and KLF4 KD increased the EDN1 production in HeLa. In conclusion, common variants in EDN1 regulatory regions could alter EDN1 levels. We were able to validate that PPARγ binds in rs397751713 and is a key regulator of EDN1. In addition, KLF4 and VDR regulate EDN1 production in a cell-dependent manner, but VDR does not bind directly to the regions we studied.

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Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

Cited by 21 publications

References 60 publications

Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model

Effects of Antidiabetic Drugs on Endothelial Function in Patients With Type 2 Diabetes Mellitus: A Bayesian Network Meta-Analysis

Common Variation in EDN1 Regulatory Regions Highlights the Role of PPARγ as a Key Regulator of Endothelin in vitro

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