Understanding the molecular targets implicated in Pulmonary Arterial Hypertension (PAH) provides critical insights into the disease's pathogenesis, progression, and therapeutic opportunities. PAH is characterized by vasoconstriction, vascular remodeling, inflammation, and thrombosis in the pulmonary arteries, leading to increased pulmonary vascular resistance and right heart failure. The targets identified here are directly involved in key pathogenic mechanisms such as aberrant vasoconstriction (e.g., endothelin and prostaglandin pathways), dysregulated cell proliferation and survival (e.g., PDGF and tyrosine kinase signaling), oxidative stress responses, and metabolic and transcriptional regulation. Collectively, these targets inform the development of disease-modifying therapies by highlighting actionable nodes in critical signaling pathways. For example, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and prostacyclin analogs are established therapies, while inhibitors of growth factor receptors and modulators of nuclear transcription factors are under investigation. The integration of these molecular insights accelerates drug discovery, supports biomarker development, and enables precision medicine approaches in PAH management.
This category includes targets that regulate vascular tone in the pulmonary circulation, directly influencing the vasoconstriction and vasodilation balance central to PAH pathogenesis. The most prominent are the endothelin receptors (EDNRA and EDNRB), which mediate potent vasoconstrictive and proliferative effects, the prostaglandin I2 receptor (PTGIR) which mediates vasodilation and antiproliferative effects, and phosphodiesterase 5A (PDE5A), which modulates cGMP signaling and thus vascular relaxation. These targets are directly implicated in PAH, with multiple approved drugs acting on these pathways.
EDNRA is a G protein-coupled receptor with seven transmembrane domains, primarily expressed on vascular smooth muscle cells. It binds endothelin-1 (ET-1) with high affinity, activating Gq/11-mediated phospholipase C signaling, leading to increased intracellular calcium, vasoconstriction, and smooth muscle proliferation. Upregulation of EDNRA and ET-1 is a hallmark of PAH, contributing to sustained vasoconstriction and vascular remodeling. Selective and dual endothelin receptor antagonists (e.g., ambrisentan, bosentan, macitentan) are approved for PAH and act by inhibiting these pathogenic effects. EDNRA expression correlates with disease severity and is a validated therapeutic and biomarker target.
EDNRB is a G protein-coupled receptor expressed on endothelial and smooth muscle cells. On endothelium, it mediates vasodilation via nitric oxide and prostacyclin release, but on smooth muscle cells, it can also mediate vasoconstriction. In PAH, dysregulated EDNRB signaling contributes to impaired vasodilation and enhanced vasoconstriction. EDNRB is targeted by dual endothelin receptor antagonists and is implicated in ET-1 clearance. Mutations or reduced expression of EDNRB are associated with PAH susceptibility. Its dual role highlights the complexity of endothelin signaling in disease.
PTGIR (IP receptor) is a G protein-coupled receptor that binds prostacyclin (PGI2), activating adenylyl cyclase and increasing cAMP, leading to vasodilation, inhibition of platelet aggregation, and antiproliferative effects on smooth muscle cells. In PAH, reduced prostacyclin synthesis and signaling contribute to vasoconstriction and vascular remodeling. Synthetic PGI2 analogs (epoprostenol, treprostinil, iloprost) and oral IP receptor agonists (selexipag) are approved therapies, restoring this protective pathway. PTGIR downregulation is observed in PAH lungs, supporting its pathogenic and therapeutic relevance.
PDE5A is a cGMP-specific phosphodiesterase highly expressed in pulmonary vascular smooth muscle. It hydrolyzes cGMP, attenuating nitric oxide-mediated vasodilation. In PAH, PDE5A is upregulated, contributing to impaired vasorelaxation. Inhibitors such as sildenafil and tadalafil increase cGMP levels, promoting vasodilation and inhibiting smooth muscle proliferation. PDE5A inhibition is a mainstay of PAH therapy, with robust clinical evidence for efficacy.
This category encompasses targets that drive abnormal proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells, leading to vascular remodeling, a core pathological feature of PAH. Key targets include platelet-derived growth factor receptors alpha and beta (PDGFRA, PDGFRB), which are tyrosine kinase receptors mediating mitogenic and anti-apoptotic signaling, and KIT proto-oncogene receptor tyrosine kinase (KIT), which is involved in progenitor cell recruitment and proliferation. These targets have been linked to disease progression and are under investigation for targeted therapies.
PDGFRA is a receptor tyrosine kinase with five extracellular immunoglobulin-like domains and an intracellular split kinase domain. Upon binding PDGF-AA, -BB, or -CC ligands, PDGFRA dimerizes and autophosphorylates, activating downstream PI3K/AKT and MAPK pathways, promoting PASMC proliferation and migration. Increased PDGFRA expression and activity are observed in PAH lesions, correlating with vascular remodeling. Imatinib, a PDGFRA/B inhibitor, has shown hemodynamic improvement in PAH clinical trials, though with safety concerns. PDGFRA is a validated pathogenic and therapeutic target.
PDGFRB is structurally similar to PDGFRA, with ligand-induced dimerization and transphosphorylation leading to activation of proliferation and survival pathways. PDGFRB is highly expressed in remodeled pulmonary arteries and perivascular cells in PAH. Its activation promotes smooth muscle hyperplasia and resistance to apoptosis. Inhibition of PDGFRB by tyrosine kinase inhibitors (imatinib, sorafenib) reduces vascular remodeling in preclinical and clinical studies. Its pathogenic role is supported by elevated PDGFRB signaling in PAH tissues.
KIT is a type III receptor tyrosine kinase with five extracellular immunoglobulin-like domains and a cytoplasmic kinase domain. Activated by stem cell factor (SCF), KIT signaling regulates progenitor cell recruitment, proliferation, and survival. Increased KIT+ progenitor cells are found in PAH vascular lesions, contributing to neointima formation and remodeling. KIT inhibition (imatinib, masitinib) reduces vascular remodeling in animal models. KIT's involvement is supported by increased expression in human and experimental PAH lungs.
This category includes targets that regulate cellular responses to oxidative stress and transcriptional programs contributing to PAH pathogenesis. NFE2 like bZIP transcription factor 2 (NFE2L2, encoding NRF2) is a master regulator of antioxidant defenses, while heme oxygenase 1 (HMOX1) is an NRF2 target with cytoprotective effects. Dysregulation of these pathways leads to oxidative injury, inflammation, and vascular remodeling in PAH.
NFE2L2 (NRF2) is a basic leucine zipper (bZIP) transcription factor that binds antioxidant response elements (AREs) in DNA. Under basal conditions, NRF2 is sequestered by KEAP1 and targeted for degradation. Upon oxidative stress, NRF2 translocates to the nucleus, inducing genes involved in antioxidant defense, detoxification, and cytoprotection. Impaired NRF2 signaling is observed in PAH, leading to increased oxidative stress, inflammation, and vascular remodeling. Pharmacological NRF2 activators (e.g., bardoxolone methyl) are under investigation for PAH. Loss-of-function mutations or reduced NRF2 activity are associated with disease severity.
HMOX1 is a stress-inducible enzyme with a heme-binding domain, catalyzing the degradation of heme to biliverdin, free iron, and carbon monoxide (CO). HMOX1 expression is regulated by NRF2 and is upregulated in response to oxidative and inflammatory stimuli. HMOX1 and its product CO exert vasodilatory, anti-inflammatory, and antiproliferative effects in the pulmonary vasculature. Reduced HMOX1 expression or activity is linked to worsened PAH in animal models and humans. Induction of HMOX1 or CO donors ameliorate experimental PAH, supporting its therapeutic potential.
Name | Short Name | Entrez Gene | KEGG | UniProtKB |
---|---|---|---|---|
ABL proto-oncogene 1, non-receptor tyrosine kinase | ABL1 | 25 | 25 | P00519 |
colony stimulating factor 1 receptor | CSF1R | 1436 | 1436 | P07333 |
component of inhibitor of nuclear factor kappa B kinase complex | CHUK | 1147 | 1147 | O15111 |
endothelin receptor type A | EDNRA | 1909 | 1909 | P25101 |
endothelin receptor type B | EDNRB | 1910 | 1910 | P24530 |
glutathione-disulfide reductase | GSR | 2936 | 2936 | P00390 |
heme oxygenase 1 | HMOX1 | 3162 | 3162 | P09601 |
insulin | INS | 3630 | 3630 | P01308 |
KIT proto-oncogene, receptor tyrosine kinase | KIT | 3815 | 3815 | P10721; A0A8I5KS03 |
NFE2 like bZIP transcription factor 2 | NFE2L2 | 4780 | 4780 | Q16236 |
peroxisome proliferator activated receptor gamma | PPARG | 5468 | 5468 | P37231 |
phosphodiesterase 5A | PDE5A | 8654 | 8654 | O76074 |
platelet derived growth factor receptor alpha | PDGFRA | 5156 | 5156 | P16234 |
platelet derived growth factor receptor beta | PDGFRB | 5159 | 5159 | P09619; A8KAM8 |
prostaglandin I2 receptor | PTGIR | 5739 | 5739 | P43119 |
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