A review of therapeutic agents for the management of pulmonary arterial hypertension

Hahn, Stella; Makaryus, Mina; Talwar, Arunabh; Narasimhan, Mangala; Zaidi, Gulrukh

doi:10.1177/1753465816665289

Cited by 11 publications

(4 citation statements)

References 95 publications

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“…The pulmonary vascular endothelium and smooth muscles are intimately implicated in the development of PAH [56, 57]. Many of the currently approved anti-PAH drugs work by increasing endothelial nitric oxide levels, an endothelium derived vesorelaxant produced by eNOS.…”

Section: Discussionmentioning

confidence: 99%

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

Rashid

Alobaida

Al-Hilal

et al. 2018

Journal of Controlled Release

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Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH.

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Section: Discussionmentioning

confidence: 99%

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

Rashid

Alobaida

Al-Hilal

et al. 2018

Journal of Controlled Release

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“…Pulmonary arterial hypertension (PAH) is a serious disease affecting the pulmonary vasculature that is characterized by the sustained elevation of pulmonary arterial pressure (>25 mmHg at rest). 68 PAH is classified as a pulmonary-selective vascular remodelling disease in which vascular smooth muscle cells display a proliferative and antiapoptotic phenotype. Pulmonary artery smooth muscle cell and pulmonary vascular endothelial cell autophagy are involved in pulmonary vascular remodelling and play an important role in the pathogenesis of PAH.…”

Section: Autophagy and Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Autophagy and pulmonary disease

Liao

Sun

et al. 2019

Ther Adv Respir Dis

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Autophagy is a process of cell self-renewal that is dependent on the degradation of the cytoplasmic proteins or organelles of lysosomes. Many diseases, such as metabolic diseases, cancer, neurodegenerative diseases, and lung diseases, have been confirmed to be associated with elevated or impaired levels of autophagy. At present, studies have found that autophagy participates in the regulation of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, acute lung injury, lung cancer, and other pulmonary diseases. Using recent literature on the signal transduction mechanisms of autophagy and the effects of autophagy signalling on lung diseases, this review intends to clarify the mechanisms of lung disease to guide the treatment of related diseases. The reviews of this paper are available via the supplemental material section.

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“…Pulmonary arterial hypertension (PAH), a rare but life-threatening dyspnoea-fatigue syndrome, which is characterized by a sustained and uncontrolled rise in pulmonary artery resistance and pulmonary vascular pressure, resulting in rapid progression of right ventricular hypertrophy, right ventricular systolic blood pressure, and eventually, heart failure and death [1,2]. At present, the pathological mechanisms of PAH are was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

Activation of peroxisome proliferator-activated receptor-γ prevents monocrotaline-induced pulmonary arterial hypertension by suppressing of nuclear factor-kappa B mediated autophagy

Zhang

Shi

Song

et al. 2023

Preprint

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To investigate the molecular mechanisms underlying autophagy inducing pulmonary vascular remodeling and rosiglitazone inhibiting pulmonary arterial hypertension (PAH). Monocrotaline (MCT) was intraperitoneally injection to induce the rat PAH model. The right ventricular hypertrophy index (RVHI), right ventricle systolic pressure (RVSP), percentage of medial wall thickness (%MT) and histomorphologic analyses were performed to evaluate the development of PAH. The translocation of nuclear factor-kappa B (NF-kappa B) p65 subunit from cytosol to nucleus, the protein expression levels of LC3B, Beclin 1 and RND3 were determined by western blot. Furthermore, NF-kappa B inhibitor, pyrrolidine dithiocarbamate (PDTC) and peroxisome proliferator-activated receptor-gamma (PPARgamma) activator, rosiglitazone, were used to inhibit the activation of NF-kappa B and activate PPARgamma signaling, respectively. MCT injection dramatically induced PAH models in rats as manifested by the increased RVSP, RVHI, and %MT. In addition, the activation of NF-kappa B and autophagy were significantly enhanced and the RND3 were markedly decreased in MCT-induced PAH in rat. However, these effects could be significantly suppressed either by the supplementation of PDTC or rosiglitazone. NF-kappa B promotes the development of PAH by activation of autophagy and consequent down-regulation of RND3 expression. Activation of PPARgamma suppresses autophagy by inhibiting NF-kappa B in MCT-induced PAH. Our results not only uncovered the mechanisms of PPARgamma activator in the protection of PAH but also provided potential therapeutic target for PAH treatment.

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A review of therapeutic agents for the management of pulmonary arterial hypertension

Cited by 11 publications

References 95 publications

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH

Autophagy and pulmonary disease

Activation of peroxisome proliferator-activated receptor-γ prevents monocrotaline-induced pulmonary arterial hypertension by suppressing of nuclear factor-kappa B mediated autophagy

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