Inhibition of Glucose-6-Phosphate Dehydrogenase Activity Attenuates Right Ventricle Pressure and Hypertrophy Elicited by VEGFR Inhibitor + Hypoxia.

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP)-a fundamental glucose metabolism pathway-is vital for cell growth. Because treatment of PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH.

Pulmonary-arterial-hypertension (PAH)-on-a-chip: fabrication, validation and application.

Currently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent in portraying the sex-disparity, and unyielding to combinatorial study designs. Here we sought to deploy the ingenuity of microengineering in developing and validating a tissue chip model for human PAH. We designed and fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery.

Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation.

Metabolic reprogramming is considered important in the pathogenesis of the occlusive vasculopathy observed in pulmonary hypertension (PH). However, the mechanisms that link reprogrammed metabolism to aberrant expression of genes, which modulate functional phenotypes of cells in PH, remain enigmatic. Herein, we demonstrate that, in mice, hypoxia-induced PH was prevented by glucose-6-phosphate dehydrogenase deficiency (G6PD), and further show that established severe PH in mice was attenuated by knockdown with G6PD shRNA or by G6PD inhibition with an inhibitor (N-ethyl-N'-[(3β,5α)-17-oxoandrostan-3-yl]urea, NEOU).

Pluripotent hematopoietic stem cells augment α-adrenergic receptor-mediated contraction of pulmonary artery and contribute to the pathogenesis of pulmonary hypertension.

Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive.

Aneurysm-type plexiform lesions form in supernumerary arteries in pulmonary arterial hypertension: potential therapeutic implications.

Histological observations in human pulmonary arterial hypertension (PAH) suggest a link between plexiform lesions and pulmonary supernumerary arteries. Pulmonary microvascular endothelial cells are characterized as hyperproliferative and progenitor-like. This study investigates the hypothesis that aneurysm-type plexiform lesions form in pulmonary supernumerary arteries because of their anatomical properties and endothelial characteristics similar to pulmonary microvascular endothelial cells.

CAR, a Homing Peptide, Prolongs Pulmonary Preferential Vasodilation by Increasing Pulmonary Retention and Reducing Systemic Absorption of Liposomal Fasudil.

Here, we sought to elucidate the role of CAR (a cyclic peptide) in the accumulation and distribution of fasudil, a drug for pulmonary arterial hypertension (PAH), in rat lungs and in producing pulmonary specific vasodilation in PAH rats. As such, we prepared liposomes of fasudil and CAR-conjugated liposomal fasudil and assessed the liposomes for CAR conjugation, physical properties, entrapment efficiencies, in vitro release profiles, and stabilities upon incubation in cell culture media, storage, and aerosolization. We also studied the cellular uptake of fasudil in different formulations, quantified heparan sulfate (HS) in pulmonary arterial smooth muscle cells (PASMCs), and investigated the distribution of the liposomes in the lungs of PAH rats.

Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac function, and arterial remodeling.

Currently, dual- or triple-drug combinations comprising different vasodilators are the mainstay for the treatment of pulmonary arterial hypertension (PAH). However, the patient outcome continues to be disappointing because the existing combination therapy cannot restrain progression of the disease. Previously, we have shown that when given as a monotherapy, long-acting inhaled formulations of sildenafil (a phosphodiesterase-5 inhibitor) and rosiglitazone (a peroxisome proliferator receptor-γ agonist) ameliorate PAH in rats.

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

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.

Pulmonary vascular dysfunction secondary to pulmonary arterial hypertension: insights gained through retrograde perfusion.

Here, we tested the hypothesis that severe pulmonary arterial hypertension impairs retrograde perfusion. To test this hypothesis, pulmonary arterial hypertension was induced in Fischer rats using a single injection of Sugen 5416 followed by 3 wk of exposure to 10% hypoxia and then 2 wk of normoxia. This Sugen 5416 and hypoxia regimen caused severe pulmonary arterial hypertension, with a Fulton index of 0.

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension.

It is widely accepted that impaired bioavailability of endothelial nitric oxide (NO) plays a critical role in the pathophysiology of pulmonary arterial hypertension (PAH). However, there are published data that show that relatively many PAH patients respond favorably to acetylcholine-induced pulmonary vasodilation during their follow-up period, when diverse stages of the disorder are included. We hypothesized that NO bioavailability varies depending on the progression of PAH Adult rats were exposed to the VEGF receptor blocker Sugen5416 and 3 weeks of hypoxia followed by return to normoxia for various additional weeks.

gene disruption is associated with increased hematopoietic stem cells: implication in chronic hypoxia-induced pulmonary hypertension.

We have recently demonstrated that disruption of the murine cytochrome -450 2c44 gene ( exacerbates chronic hypoxia-induced pulmonary artery remodeling and hypertension in mice. Subsequently, we serendipitously found that gene disruption also increases hematopoietic stem cell (HSC) numbers in bone marrow and blood. Therefore, the objective of the present study was to investigate whether CYP2C44-derived eicosanoids regulate HSC proliferation/cell growth and whether increased HSCs contribute to chronic hypoxia-induced remodeling of pulmonary arteries in knockout mice.

Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH).

The practice of treating PAH patients with oral or intravenous sildenafil suffers from the limitations of short dosing intervals, peripheral vasodilation, unwanted side effects, and restricted use in pediatric patients. In this study, we sought to test the hypothesis that inhalable poly(lactic-co-glycolic acid) (PLGA) particles of sildenafil prolong the release of the drug, produce pulmonary specific vasodilation, reduce the systemic exposure of the drug, and may be used as an alternative to oral sildenafil in the treatment of PAH. Thus, we prepared porous PLGA particles of sildenafil using a water-in-oil-in-water double emulsion solvent evaporation method with polyethyleneimine (PEI) as a porosigen and characterized the formulations for surface morphology, respirability, in-vitro drug release, and evaluated for in vivo absorption, alveolar macrophage uptake, and safety.

Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.

Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR.

Sphingosine-1-phosphate is involved in the occlusive arteriopathy of pulmonary arterial hypertension.

Despite several advances in the pathobiology of pulmonary arterial hypertension (PAH), its pathogenesis is not completely understood. Current therapy improves symptoms but has disappointing effects on survival. Sphingosine-1-phosphate (S1P) is a lysophospholipid synthesized by sphingosine kinase 1 (SphK1) and SphK2.

Cyp2c44 gene disruption exacerbated pulmonary hypertension and heart failure in female but not male mice.

Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH.

How does pulmonary endarterectomy cure CTEPH: A clue to cure PAH?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a hot topic in the field of pulmonary hypertension, because many CTEPH patients are now curable by surgical pulmonary endarterectomy and more recently possibly by pulmonary balloon angioplasty. However, there are still uncertainties regarding the pathogenesis of CTEPH, specifically how and where the small vessel arteriopathy that is indistinguishable from that in pulmonary arterial hypertension (plexogenic arteriopathy) develops, and how pulmonary endarterectomy improves hemodynamics and possibly cures CTEPH. Based on our recent experimental finding that hemodynamic stress is fundamental for the development of plexogenic arteriopathy, we discuss the uncertainties of CTEPH and potential implication of the effectiveness of pulmonary endarterectomy for reversing plexogenic arteriopathy and possibly providing a novel approach to cure pulmonary arterial hypertension.

MicroRNA-140 is elevated and mitofusin-1 is downregulated in the right ventricle of the Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension.

Heart failure, a major cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), is an outcome of complex biochemical processes. In this study, we determined changes in microRNAs (miRs) in the right and left ventricles of normal and PAH rats. Using an unbiased quantitative miR microarray analysis, we found 1) miR-21-5p, miR-31-5 and 3p, miR-140-5 and 3p, miR-208b-3p, miR-221-3p, miR-222-3p, miR-702-3p, and miR-1298 were upregulated (>2-fold; P < 0.

Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension.

Aims: An important pathogenic mechanism in the development of idiopathic pulmonary arterial hypertension is hypothesized to be a cancer-like cellular proliferation independent of haemodynamics. However, because the vascular lesions are inseparably coupled with haemodynamic stress, the fate of the lesions is unknown when haemodynamic stress is eliminated.

Methods And Results: We applied left pulmonary artery banding to a rat model with advanced pulmonary hypertension to investigate the effects of decreased haemodynamic stress on occlusive vascular lesions.

Chronic hypoxia does not cause wall thickening of intra-acinar pulmonary supernumerary arteries.

Chronic exposure to hypoxia causes pulmonary hypertension and pulmonary arterial remodeling. Although the exact mechanisms of this remodeling are unclear, there is evidence that it is dependent on hemodynamic stress, rather than on hypoxia alone. Pulmonary supernumerary arteries experience low hemodynamic stress as a consequence of reduced perfusion due to 90° branching angles, small diameters, and "valve-like" structures at their orifices.

Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension.

Therapies that exploit RNA interference (RNAi) hold great potential for improving disease outcomes. However, there are several challenges that limit the application of RNAi therapeutics. One of the most important challenges is effective delivery of oligonucleotides to target cells and reduced delivery to non-target cells.

Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension.

Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells.

Peptide-coated liposomal fasudil enhances site specific vasodilation in pulmonary arterial hypertension.

This study sought to develop a liposomal delivery system of fasudil--an investigational drug for the treatment of pulmonary arterial hypertension (PAH)--that will preferentially accumulate in the PAH lungs. Liposomal fasudil was prepared by film-hydration method, and the drug was encapsulated by active loading. The liposome surface was coated with a targeting moiety, CARSKNKDC, a cyclic peptide; the liposomes were characterized for size, polydispersity index, zeta potential, and storage and nebulization stability.

Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure.

Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease with no known cure. Heart failure is a major comorbidity and a common cause of the premature death of patients with PAH. Increased asymmetrical right ventricular hypertrophy and septal wall thickening compress the left ventricular cavity and elicit diastolic heart failure.

Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats.

Although hypoxia is detrimental to most cell types, it aids survival of progenitor cells and is associated with diseases like cancer and pulmonary hypertension in humans. Therefore, understanding the underlying mechanisms that promote survival of progenitor cells in hypoxia and then developing novel therapies to stop their growth in hypoxia-associated human diseases is important. Here we demonstrate that the proliferation and growth of human CD133(+) progenitor cells, which contribute to tumorigenesis and the development of pulmonary hypertension, are increased when cultured under hypoxic conditions.