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Role of Transcription Factors in Pulmonary Artery Smooth Muscle Cells: An Important Link to Hypoxic Pulmonary Hypertension

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Pulmonary Vasculature Redox Signaling in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 967))

Abstract

Hypoxia, namely a lack of oxygen in the blood, induces pulmonary vasoconstriction and vasoremodeling, which serve as essential pathologic factors leading to pulmonary hypertension (PH). The underlying molecular mechanisms are uncertain; however, pulmonary artery smooth muscle cells (PASMCs) play an essential role in hypoxia-induced pulmonary vasoconstriction, vasoremodeling, and PH. Hypoxia causes oxidative damage to DNAs, proteins, and lipids. This damage (oxidative stress) modulates the activity of ion channels and elevates the intracellular calcium concentration ([Ca2+]i, Ca2+ signaling) of PASMCs. The oxidative stress and increased Ca2+ signaling mutually interact with each other, and synergistically results in a variety of cellular responses. These responses include functional and structural abnormalities of mitochondria, sarcoplasmic reticulum, and nucleus; cell contraction, proliferation, migration, and apoptosis, as well as generation of vasoactive substances, inflammatory molecules, and growth factors that mediate the development of PH. A number of studies reveal that various transcription factors (TFs) play important roles in hypoxia-induced oxidative stress, disrupted PAMSC Ca2+ signaling and the development and progress of PH. It is believed that in the pathogenesis of PH, hypoxia facilitates these roles by mediating the expression of multiple genes. Therefore, the identification of specific genes and their transcription factors implicated in PH is necessary for the complete understanding of the underlying molecular mechanisms. Moreover, this identification may aid in the development of novel and effective therapeutic strategies for PH.

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Abbreviations

[Ca2+]i :

Intracellular calcium concentration

AP-1:

Activator protein-1

BKCa :

Ca2+-activated potassium channel

C/EBP:

CCAAT/enhancer binding protein

CaMK:

Ca2+/calmodulin-dependent protein kinase

CBP:

CREB binding protein

CCL11:

C-C motif chemokine 11

COPD:

Chronic obstructive pulmonary disease

CREB:

cAMP response element-binding protein

CS:

Cigarette smoke

CXCL:

Chemokine ligand

ET-1:

Endothelin-1

ETC:

Electron-transport chain

FOXO:

Forkhead box protein O

GATA:

Erythroid transcription factor

HDAC2:

Histone deacetylase 2

HIF-1:

Hypoxia inducible factor-1

IFN:

Interferon

IgE:

Immunoglobulin E

IKK:

IκB kinase

IL:

Interleukin

IP3R:

Inositol triphosphate receptor

IκB:

Inhibitor of NF-κB

JNK:

jun-N-terminal kinase

MEF:

Myocyte enhancer factor

NFAT:

Nuclear factor of activated T lymphocytes

NF-κB:

Nuclear factor-κB

Nox:

NADPH oxidase

NRF2:

Nuclear erythroid 2-related factor 2

PAEC:

Pulmonary artery endothelial cell

PASMC:

Pulmonary artery smooth muscle cell

PDGFR:

Platelet-derived growth factor receptor

PH:

Pulmonary hypertension

PKC:

Protein kinase C

PPAR:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

SOCE:

Store-operated Ca2+ entry

SOCS:

Suppressor of cytokine signaling

SR:

Sarcoplasmic reticulum

SRF:

Serum response factor

STAT:

Signal transducers and activators of transcription

TAK:

Transforming growth factor activating kinase

TBP:

TATA binding protein

TF:

Transcription factor

Th2:

T-helper type-2

TNF:

Tumor necrosis factor

Treg:

Regulatory T cells

VDCC:

Voltage-dependent Ca2+ channel

VEGF:

Vascular endothelial growth factor

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  1. Department of Molecular & Cellular Physiology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA

    Annarita Di Mise, Yong-Xiao Wang & Yun-Min Zheng

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Di Mise, A., Wang, YX., Zheng, YM. (2017). Role of Transcription Factors in Pulmonary Artery Smooth Muscle Cells: An Important Link to Hypoxic Pulmonary Hypertension. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_2

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