The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Abstract

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat

“…(38, 39). In addition, the JAK/STAT activation is involved in the proliferation, migration, senescence, and transformation of endothelial cells and PASMCs into mesenchymal/myofibroblast cells (40). JAK2/STAT3 pathways are involved in the regulation of hypoxia-mediated vascular remodeling by inhibiting PASMC proliferation and hyperplasia (33,(40)(41)(42).…”

“…In addition, the JAK/STAT activation is involved in the proliferation, migration, senescence, and transformation of endothelial cells and PASMCs into mesenchymal/myofibroblast cells (40). JAK2/STAT3 pathways are involved in the regulation of hypoxia-mediated vascular remodeling by inhibiting PASMC proliferation and hyperplasia (33,(40)(41)(42). Taking the role of the three pathways in inflammation or pulmonary vascular remodeling in PAH into account, we considered that notopterol may act through one of them.…”

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

“…JAK/STAT pathway begins with the autophosphorylation/activation of the receptor-associated tyrosine kinases JAK by binding a ligand (growth factors, interferon or cytokines) to its cognate transmembrane receptor. JAK then recruits and phosphorylate/activate STAT proteins, which translocate into the nucleus and promote the transcription of target genes [ 184 , 185 , 186 ]. Increasing evidence suggests prominent JAK/STAT activation in cultured SSc fibroblasts, in SSc dermal and lung biopsies and in experimental scleroderma [ 187 , 188 , 189 ].…”

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

“…The hyperactivation of JAK-STAT has been highlighted in the aforementioned diseases, but more recently, it has also been reported in patients with pulmonary hypertension (PH): in their isolated pulmonary arteries, JAK2 and STAT3 mRNA transcript levels and protein expressions were higher than those in health subjects (Roger et al, 2021). In cancer, the hyperactivation of this pathway can be either due to a JAK mutation, as mostly observed in some hematological malignancies (Vainchenker and Constantinescu, 2013), or due to the intrinsic nature of cancer, as in some solid tumors (Qureshy et al, 2020).…”

“…Aberrant activation of JAK-STAT is encountered in many immune-mediated diseases ( Jamilloux et al, 2019 ), including rheumatoid arthritis (RA) ( Malemud, 2018 ), systemic lupus erythematosus (SLE) ( Goropevšek et al, 2017 ), psoriatic arthritis (PsA) ( Fiocco et al, 2014 ), psoriasis ( Kwatra et al, 2012 ), inflammatory bowel disease (IBD) ( Salas et al, 2020 ), Crohn’s disease, ulcerative colitis ( Rogler, 2020 ), discoid lupus erythematosus (DLE), and dermatomyositis (DM) ( Kahn et al, 2018 ). The hyperactivation of JAK-STAT has been highlighted in the aforementioned diseases, but more recently, it has also been reported in patients with pulmonary hypertension (PH): in their isolated pulmonary arteries, JAK2 and STAT3 mRNA transcript levels and protein expressions were higher than those in health subjects ( Roger et al, 2021 ). In cancer, the hyperactivation of this pathway can be either due to a JAK mutation, as mostly observed in some hematological malignancies ( Vainchenker and Constantinescu, 2013 ), or due to the intrinsic nature of cancer, as in some solid tumors ( Qureshy et al, 2020 ).…”