Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

Keywords: BMP signaling; endothelial dysfunction; epigenetics; inflammation; mitochondrial dysfunction; pulmonary arterial hypertension; tyrosine kinase receptor; vascular remodeling.

Figure 1

Main molecular mechanisms involved in the pathobiology of pulmonary arterial hypertension. BMP: bone morphogenic protein; PAH: pulmonary arterial hypertension.

Figure 2

BMP signaling pathway. (A). Dysregulation of the BMP signaling pathway produces an imbalance between anti-proliferative and pro-proliferative routes in pulmonary arterial hypertension. Decreased BMPR2 activity leads to reduced BMP9/10-mediated signaling, diminished activation of Smad1/5/8 and reduction in the transcription of anti-proliferative genes, causing an increase in apoptosis and loss of the endothelial barrier integrity. This promotes the upregulation of pro-proliferative routes by production of activin A and GDF that bind to the ALK—ActRIIA/B complex and activate the pro-proliferative Smad2/3 pathway. This route also increases the expression of the BMP antagonists, gremlin-1 and noggin, further downregulating the BMPR2 pathway. (B). Sotatercept is a fusion protein comprising the extracellular domain of the activin receptor type IIA attached to the Fc domain of human IgG1. It acts as a ligand trap by binding activins and GDF and thereby restoring the balance between pro-proliferative and anti-proliferative BMP pathways. ActRIIA/B: activin receptor type IIA; ALK: activin receptor-like kinase; BMP: bone morphogenic protein; BMPR2: bone morphogenic protein receptor type-2; GDF: growth differentiation factor; pSmad: phosphorylated Smad; Smad: small mothers against decapentaplegic protein.

Figure 3

Tyrosine kinase receptor signaling. (A). Upregulation of the tyrosine kinase receptor PDGFR and its ligand, platelet-derived growth factor, which is the most potent mitogenic for vascular smooth muscle cells, has been observed in pulmonary arterial hypertension. Ligand binding of platelet-derived growth factor induces dimerization of the receptors followed by activation by autophosphorylation and downstream signaling and transcription of pro-proliferative genes. This leads to excessive proliferation of vascular smooth muscle cells in the arteriolar media and myofibroblasts in the vessel lumen, with media hypertrophy and intimal fibrosis. CSFIR and c-KIT are two additional PDGFR-related kinases that have also been involved in the pathobiology of PAH. CSF1R is expressed on monocytes and macrophages, which secrete platelet-derived growth factor ligands and inflammatory cytokines, promoting inflammation and remodeling of the pulmonary vasculature. C-KIT is expressed on endothelial progenitor cells and mast cells, and it is thought to play a role in perivascular inflammation and vascular remodeling. (B). RTKA reduce the upregulation of the pro-proliferative tyrosine kinase receptor-dependent signaling pathways. The RTKA imatinib inhibits PDGFR, DDR, c-KIT, CSF1R and ABL. The RTKA seralutinib inhibits PDGFR, CSF1R, and c-KIT, and increases bone morphogenetic protein receptor type-2. (C). Oral (left) and inhaled (right) administration of RTKA. (D). The inhaled formulation of the RTKA delivers high concentrations of the compound throughout the airways that reaches the pulmonary vasculature and the surrounding tissues to exert their anti-proliferative effects. ABL: abelson tyrosine kinase; CSF1R: colony stimulating factor 1 receptor; DDR: discoidin domain receptor tyrosine kinase; HCK: hematopoietic cell kinase; LCK: lymphocyte-specific protein tyrosine kinase; PDGFR: platelet-derived growth factor receptor; RET: rearranged during transfection tyrosine kinase; RTKA: receptor tyrosine kinase antagonist; SRC: sarcoma tyrosine kinase; VEGFR: vascular endothelial growth factor receptor.