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

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 ([Ca], Ca signaling) of PASMCs. The oxidative stress and increased Ca 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 Ca 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.

Oxidative Stress and Diseases Associated with High-Altitude Exposure

“…Studies have shown that oxidative stress or exacerbated levels of ROS (specifically superoxide and hydrogen peroxide) are necessary to increase [Ca 2+ ] i under hypoxic conditions; this concentration increase is realized through voltage-dependent calcium channels (VDCCs) in PASMCs [ 89 , 90 , 91 ] and causes PASMC contraction and increases in pulmonary artery pressure.…”

Identification of Crucial Hub Genes and Differential T Cell Infiltration in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Strategies

“…Precise transcriptional regulation of protein-encoding genes is critical for cell proliferation, differentiation, and development ( Thomas and Chiang, 2006 ). TFs are considered to play vital roles in the development of pulmonary hypertension through pro-inflammatory, immunological, and multiple other cellular responses ( Di Mise et al, 2017 ). To our knowledge, this is the first study to show that TFs RBBP9, GATA3, and TAF1 may be involved in the development of IPAH.…”

The potential role of TRPV1 in pulmonary hypertension: Angel or demon?

“…The expression of c-jun and c-fos can be upregulated by calcium influx and is much higher in lung vessels from IPAH patients and modeled PAH rats than normal. Therefore, the Ca 2+ /c-jun and c-fos pathway may also be a signaling pathway for PASMCs proliferation [29,39]. Although there is no evidence that TRPV1 is responsible for this pathway, we cannot exclude the existence of the TRPV1/Ca 2+ /c-jun(c-fos) pathway in PAH; further investigation is needed.…”

“…CREB is a Ca 2+ -dependent TF that modulates gene expression by binding to the promoter region of target genes after translocating into the nucleus. This translocation necessitates its phosphorylation by Ca 2+ /CaM-dependent protein kinase II and Ca 2 + /CaM-dependent protein kinase IV [27,29]. The pCREB has been found to be significantly upregulated in IPAH PASMCs, accompanied by increased TRPV1 and [Ca 2+ ] i .…”

“…[Ca 2+ ] i can cause PASMCs contraction by allowing actin to activate the myosin ATP ase in a Ca 2+ -calmodulin (CaM) -myosin light chain kinase (MLCK) -myosin regulatory light chain (RLC) pathway and promote PASMCs proliferation and migration by stimulating transcription factors (TFs), which constitute the important foundation of PAH primely [27][28][29]. There are many TFs contributing to PASMCs proliferation and migration, some of which are Ca 2+dependent, such as nuclear factor of activated T lymphocytes (NFAT), cAMP response elementbinding protein (CREB) and activator protein-1 (AP-1) [27,29].…”