Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

Nozik‐Grayck, Eva; Woods, Crystal; Stearman, Robert S.; Venkataraman, Sujatha; Ferguson, Bradley S.; Swain, Kalin; Bowler, Russell P.; Geraci, Mark W.; Ihida-Stansbury, Kaori; Stenmark, Kurt R.; McKinsey, Timothy A.; Domann, Frederick E.

doi:10.1152/ajplung.00263.2015

Cited by 42 publications

(36 citation statements)

References 58 publications

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“…While overexpression of EC-SOD attenuated (172), and total body loss of EC-SOD accentuated (271), hypoxic PH, the results from conditional EC-SOD deletion suggest that EC-SOD bound to SMC may be a key regulator of oxidant-induced injury in the CH model of PH. These findings are consistent with recent work demonstrating reduction in EC-SOD expression in lung tissue and PASMCs from PAH patients mediated by histone deacetylation (173).…”

Section: Pathways and Targetssupporting

confidence: 93%

Update on novel targets and potential treatment avenues in pulmonary hypertension

Huetsch

Suresh

Bernier

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension (PH) is a condition marked by a combination of constriction and remodeling within the pulmonary vasculature. It remains a disease without a cure, as current treatments were developed with a focus on vasodilatory properties but do not reverse the remodeling component. Numerous recent advances have been made in the understanding of cellular processes that drive pathologic remodeling in each layer of the vessel wall as well as the accompanying maladaptive changes in the right ventricle. In particular, the past few years have yielded much improved insight into the pathways that contribute to altered metabolism, mitochondrial function, and reactive oxygen species signaling and how these pathways promote the proproliferative, promigratory, and antiapoptotic phenotype of the vasculature during PH. Additionally, there have been significant advances in numerous other pathways linked to PH pathogenesis, such as sex hormones and perivascular inflammation. Novel insights into cellular pathology have suggested new avenues for the development of both biomarkers and therapies that will hopefully bring us closer to the elusive goal: a therapy leading to reversal of disease.

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Section: Pathways and Targetssupporting

confidence: 93%

Update on novel targets and potential treatment avenues in pulmonary hypertension

Huetsch

Suresh

Bernier

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Further experimentation would help clarify the findings of Zhao et al, who identified the increased expression of HDAC1/4/5 in lungs from human idiopathic PAH, but only focused on the role of HDAC1/5 in remodeled pulmonary vessels . Nozik‐Grayck and colleagues found that HDAC3 induced the suppression of superoxide dismutase (ie, superoxide dismutase 3) in PASMCs and suggested that the HDAC pan‐inhibitor Trichostatin A (TSA) may protect against idiopathic PAH, in part, by blocking HDAC3 activity and increasing PASMC superoxide dismutase 3 expression …”

Section: Discussionmentioning

confidence: 99%

“…63 Nozik-Grayck and colleagues found that HDAC3 induced the suppression of superoxide dismutase (ie, superoxide dismutase 3) in PASMCs and suggested that the HDAC pan-inhibitor Trichostatin A (TSA) may protect against idiopathic PAH, in part, by blocking HDAC3 activity and increasing PASMC superoxide dismutase 3 expression. 64 To elucidate the regulatory mechanisms of the miR-1281/ HDAC4 pathway, 2 possible actions of HDAC4 were considered: it may be globally influencing the PASMC transcriptome by altering the acetylation status of histone(s), or it may be specifically interacting with related commanding transcription factors. The data from our study support the latter case.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3‐Kinase–DNA Methyltransferase 1–miR‐1281–Histone Deacetylase 4 Regulatory Axis Mediates Platelet‐Derived Growth Factor–Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

Qian

et al. 2018

JAHA

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BackgroundPlatelet‐derived growth factor BB, a potent mitogen of pulmonary artery smooth muscle cells (PASMCs), has been implicated in pulmonary arterial remodeling, which is a key pathogenic feature of pulmonary arterial hypertension. Previous microRNA profiling in platelet‐derived growth factor BB–treated PASMCs found a significantly downregulated microRNA, miR‐1281, but it has not been associated with any cellular function, and we investigated the possibility.Methods and ResultsReal‐time quantitative reverse transcription–polymerase chain reaction assay proved that downregulation of miR‐1281 was a conserved phenomenon in human and rat PASMCs. Overexpression and inhibition of miR‐1281 in PASMCs promoted and suppressed, respectively, the cell proliferation and migration. Bioinformatic prediction and 3′‐untranslated region reporter assay identified histone deacetylase 4 to be a direct target of miR‐1281. Supporting this, proliferation and migration assay demonstrated the cellular function of histone deacetylase 4 is inversely correlated with that of miR‐1281. Mechanistically, it is found that platelet‐derived growth factor BB activates the phosphatidylinositol 3‐kinase pathway, which then induces the expression of DNA methyltransferase 1, leading to enhanced methylation of a flanking CpG island and repressed miR‐1281 expression. Finally, a reduced miR‐1281 level was consistently identified in hypoxic PASMCs in vitro, in pulmonary arteries of rats with monocrotaline‐induced pulmonary arterial hypertension, and in serum of patients with coronary heart disease–pulmonary arterial hypertension. These data suggest that there may be a diagnostic and therapeutic use for miR‐1281.ConclusionsHerein, we report a novel regulatory axis, phosphatidylinositol 3‐kinase–DNA methyltransferase 1–miR‐1281–histone deacetylase 4, integrating multiple epigenetic regulators that participate in platelet‐derived growth factor BB–stimulated PASMC proliferation and migration and pulmonary vascular remodeling.

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“…Inhibitors against histone acetyltransferases (HATs), such as GCN5, p300, and PCAF, prevented EcSOD increases in a stimulated monocytic leukemia cell line, THP-1 [170]. Additionally, several studies have demonstrated increased EcSOD expression with histone deacetylase (HDAC) inhibitors [116 170 171 179 180]. Specifically, inhibition or knockdown of HDAC3 led to increased EcSOD expression in pulmonary artery smooth muscle cells [179].…”

Section: Deregulation Of Ecsod In Cancersmentioning

confidence: 99%

“…Additionally, several studies have demonstrated increased EcSOD expression with histone deacetylase (HDAC) inhibitors [116 170 171 179 180]. Specifically, inhibition or knockdown of HDAC3 led to increased EcSOD expression in pulmonary artery smooth muscle cells [179]. HDAC3 is up-regulated in many solid cancers, such as lung, breast, pancreatic, liver, and colon, indicating another potential mechanism of EcSOD silencing in cancer [181–185].…”

Section: Deregulation Of Ecsod In Cancersmentioning

confidence: 99%

Extracellular superoxide dismutase and its role in cancer

Griess

Tom

Domann

et al. 2017

Free Radical Biology and Medicine

150

124

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Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is a relatively new comer in terms of its tumor suppressive role in cancer and the mechanisms involved are less well understood. Nevertheless, the degree of differential expression of this extracellular antioxidant in cancer versus normal cells/tissues is more pronounced and prevalent than the other SODs. A significant association of low EcSOD expression with reduced cancer patient survival further suggests that loss of extracellular redox regulation promotes a conducive microenvironment that favors cancer progression. The vast array of mechanisms reported in mediating deregulation of EcSOD expression, function, and cellular distribution also supports that loss of this extracellular antioxidant provides a selective advantage to cancer cells. Moreover, overexpression of EcSOD inhibits tumor growth and metastasis, indicating a role as a tumor suppressor. This review focuses on the current understanding of the mechanisms of deregulation and tumor suppressive function of EcSOD in cancer.

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Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

Cited by 42 publications

References 58 publications

Update on novel targets and potential treatment avenues in pulmonary hypertension

Update on novel targets and potential treatment avenues in pulmonary hypertension

Phosphatidylinositol 3‐Kinase–DNA Methyltransferase 1–miR‐1281–Histone Deacetylase 4 Regulatory Axis Mediates Platelet‐Derived Growth Factor–Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

Extracellular superoxide dismutase and its role in cancer

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