Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension

Zhang, Hui; D’Alessandro, Angelo; Li, Min; Reisz, Julie A.; Riddle, Suzette; Muralidhar, Akshay; Bull, Todd; Zhao, Lan; Gerasimovskaya, Evgenia; Stenmark, Kurt R.

doi:10.1016/j.vph.2023.107157

Cited by 7 publications

(8 citation statements)

References 53 publications

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“…In addition to the effect on glycolysis, low PK enzymatic activity, as would occur when PKM2 is preponderant, has been proposed to divert glycolytic intermediates toward biosynthetic pathways such as the pentose phosphate pathway and serine biosynthesis [111]. Consistent with these studies, steady-state and U-13C-glucose-tracing metabolomics analyses in PH-Fibs (having an increased PKM2/PKM1 ratio) indicated increased pentose phosphate pathway activation and serine biosynthesis and significantly increased purine synthesis [112]. Importantly, it was reported that TEPP-46 or histone deacetylase inhibitors (HDACis) downregulated the substrates of purine de novo synthesis (serine and ribose) and thus purines in PH-Fibs through promoting PKM activity.…”

Section: Role Of Dysregulated Mirnas Underlying Ph-fib Abnormalitiesmentioning

confidence: 71%

“…A synergic therapeutic effect was observed when an HDACi was combined with a well-known vasodilator and a mainstay in the treatment of PH, sildenafil, in correcting metabolic reprogramming and inhibiting the proliferation of PH-Fibs [112]. In summary, the studies by Wang et al and Zhang et al reveal how miR-124 regulates PH-Fib phenotypes and provide multiple targets for the development of therapeutic strategies (e.g., HDACi, miR-124 mimics, PTBP1 inhibitors, or PKM2 activators) for the treatment of PH, which are summarized in Figure 2 [10,110,112,113]. In addition to the critical role of miR-124 in PA adventitial fibroblasts in PH, Luo Y and colleagues found that activated PAAFs promoted pulmonary vascular remodeling via miR-29a reduction in a chronic hypoxia rat PH model by regulating the levels of a-smooth muscle actin (a-SMA) and ECM collagen.…”

Section: Role Of Dysregulated Mirnas Underlying Ph-fib Abnormalitiesmentioning

confidence: 99%

“…Importantly, it was reported that TEPP-46 or histone deacetylase inhibitors (HDACis) downregulated the substrates of purine de novo synthesis (serine and ribose) and thus purines in PH-Fibs through promoting PKM activity. A synergic therapeutic effect was observed when an HDACi was combined with a well-known vasodilator and a mainstay in the treatment of PH, sildenafil, in correcting metabolic reprogramming and inhibiting the proliferation of PH-Fibs [ 112 ]. In summary, the studies by Wang et al and Zhang et al reveal how miR-124 regulates PH-Fib phenotypes and provide multiple targets for the development of therapeutic strategies (e.g., HDACi, miR-124 mimics, PTBP1 inhibitors, or PKM2 activators) for the treatment of PH, which are summarized in Figure 2 [ 10 , 110 , 112 , 113 ].…”

Section: Mechanisms Underlying Fibroblast Abnormalities In Phmentioning

confidence: 99%

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Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Zhang,

Li,

et al. 2024

Cells

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Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.

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Section: Role Of Dysregulated Mirnas Underlying Ph-fib Abnormalitiesmentioning

confidence: 71%

Section: Role Of Dysregulated Mirnas Underlying Ph-fib Abnormalitiesmentioning

confidence: 99%

Section: Mechanisms Underlying Fibroblast Abnormalities In Phmentioning

confidence: 99%

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Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Zhang,

Li,

et al. 2024

Cells

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“…Recent studies determined that fibroblasts from PH patients treated with combined therapy of sildenafil (vasodilator) and HDAC inhibitor exhibited synergistic inhibitory effects on PH-fibroblast proliferation and induced metabolic reprogramming [21]. A recent study in multiple PH models suggests that pharmacological inhibition of the P300/CREBbinding transcriptional co-activators and histone acetyl transferase (HAT) complex rescues distal pulmonary vascular remodeling and hemodynamics in PH models as well as the vascular remodeling in precision-cut tissue slices from human PH lungs ex vivo [22].…”

Section: Adventitial Fibroblastsmentioning

confidence: 99%

Emerging Epigenetic Targets and Their Molecular Impact on Vascular Remodeling in Pulmonary Hypertension

Ranasinghe,

Tennakoon,

Schwarz

2024

Cells

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Pulmonary Hypertension (PH) is a terminal disease characterized by severe pulmonary vascular remodeling. Unfortunately, targeted therapy to prevent disease progression is limited. Here, the vascular cell populations that contribute to the molecular and morphological changes of PH in conjunction with current animal models for studying vascular remodeling in PH will be examined. The status quo of epigenetic targeting for treating vascular remodeling in different PH subtypes will be dissected, while parallel epigenetic threads between pulmonary hypertension and pathogenic cancer provide insight into future therapeutic PH opportunities.

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“…Purine biosynthesis plays a key role in adverse pulmonary vasculature remodeling associated with PH. While sildenafil alone only modestly reverses purine biosynthesis, a combination therapy with histone deacetylase inhibitors showed inhibitory effects on purine synthesis, representing a novel and, potentially, more efficacious approach against the constriction of blood vessels and their adverse remodeling [36].…”

Section: Specific Ph Subtypesmentioning

confidence: 99%

Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology

Bassareo,

D’Alto

2023

IJMS

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Pulmonary hypertension (PH) is a multifaceted illness causing clinical manifestations like dyspnea, fatigue, and cyanosis. If left untreated, it often evolves into irreversible pulmonary arterial hypertension (PAH), leading to death. Metabolomics is a laboratory technique capable of providing insights into the metabolic pathways that are responsible for a number of physiologic or pathologic events through the analysis of a biological fluid (such as blood, urine, and sputum) using proton nuclear magnetic resonance spectroscopy or mass spectrometry. A systematic review was finalized according to the PRISMA scheme, with the goal of providing an overview of the research papers released up to now on the application of metabolomics to PH/PAH. So, eighty-five papers were identified, of which twenty-four concerning PH, and sixty-one regarding PAH. We found that, from a metabolic standpoint, the hallmarks of the disease onset and progression are an increase in glycolysis and impaired mitochondrial respiration. Oxidation is exacerbated as well. Specific metabolic fingerprints allow the characterization of some of the specific PH and PAH subtypes. Overall, metabolomics provides insights into the biological processes happening in the body of a subject suffering from PH/PAH. The disarranged metabolic pathways underpinning the disease may be the target of new therapeutic agents. Metabolomics will allow investigators to make a step forward towards personalized medicine.

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Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension

Cited by 7 publications

References 53 publications

Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Emerging Epigenetic Targets and Their Molecular Impact on Vascular Remodeling in Pulmonary Hypertension

Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology

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