Pulmonary artery hypertension in childhood: The transforming growth factor-β superfamily-related genes

Abstract

Pulmonary artery hypertension (PAH) is very rare in childhood, and it can be divided into heritable, idiopathic drug- and toxin-induced and other disease (connective tissue disease, human immunodeficiency virus infection, portal hypertension, congenital heart disease, or schistosomiasis)-associated types. PAH could not be interpreted solely by pathophysiological theories. The impact of the transforming growth factor-β superfamily-related genes on the development of PAH in children remains to be clarified. Pertinent literature on the transforming growth factor-β superfamily-related genes in relation to PAH in children published after the year 2000 was reviewed and analyzed. Bone morphogenetic protein receptor type II gene mutation promotes cell division or prevents cell death, resulting in an overgrowth of cells in small arteries throughout the lungs. About 20% of individuals with a bone morphogenetic protein receptor type II gene mutation develop symptomatic PAH. In heritable PAH, bone morphogenetic protein receptor type II mutations may be absent; while mutations of other genes, such as type I receptor activin receptor-like kinase 1 and the type III receptor endoglin (both associated with hereditary hemorrhagic telangiectasia), caveolin-1 and KCNK3, the gene encoding potassium channel subfamily K, member 3, can be detected, instead. Gene mutations, environmental changes and acquired adjustment, etc. may explain the development of PAH. The researches on PAH rat model and familial PAH members may facilitate the elucidations of the mechanisms and further provide theories for prophylaxis and treatment of PAH.

Interleukin-13 in the pathogenesis of pulmonary artery hypertension

“…Besides, mutations, environmental changes and acquired adjustment of transforming growth factor (TGF)-β superfamilyrelated genes may explain at least partly the mechanisms of congenital PAH [12][13][14]. In these studies, it was revealed that an imbalance of vascular cellular proliferation, driven by stimulation of excessive growth factors, such as TGF-β family signaling, platelet derived growth factor (PDGF) and Notch receptor play an important role in the development of PAH [15]. It has been noted that, in the developmental course of PAH, the immune cells initiate and maintain inflammatory responses to infections [16,17], and to hypoxic insults of the lung [18,19].…”

Interleukin-6 in pulmonary artery hypertension

“…These results indicated that the inflammatory cytokine IL-6 might contribute to PAH in COPD and that IL-6 gene polymorphism endorses susceptibility to patients with PAH secondary to COPD. BMPR2 gene mutation might boost cell division and prevent cell death, leading to pulmonary vascular remodeling, and one-fifth of individuals with a BMPR2 gene mutation might progress into PAH [36]. Thus, BMPR2 gene mutations constitute the background of the pathogenesis of heritable PAH [37].…”

Genetic Basis of Human Congenital Heart Disease

“…Isolated CHD lesions associated with NODAL mutations include D-TGA, double outlet right ventricle (DORV), TOF, and isolated VSDs. Overexpression of TGF-β1 seems to play a role in the development of pulmonary hypertension in patients with CHD, suggesting that alterations in this pathway may have pleo- tropic effects on the heart as well as the pulmonary vasculature (Gao et al 2005;Yuan 2018).…”