Table 1 The therapeutic strategies targeting signaling pathways for PH
From: Signaling pathways and targeted therapy for pulmonary hypertension
THERAPEUTIC | INTERVENTION | TARGET | DISEASE | Group | EFFECT | REFERENCE | |
|---|---|---|---|---|---|---|---|
STRATEGY | PATHWAY | (MODELS) | (PH) | Hemodynamic | Pathological | ||
Cell therapy | Preconditioned MSCs with PGE1 | Activates HIF-1α | MCT-PAH rat | Group 1 | Decreases mPAP | Inhibits MSC apoptosis and promotes the migration of MSCs to the injury site | |
Medium from M2b macrophages | Inhibits PI3K/Akt | MCT-PAH rat | Group 1 | / | Promotes apoptosis, inhibits PASMC proliferation and migration | ||
Modified SCs to overproduce FGF2 | Activates PI3K/Akt | MCT-PAH rat, MCTP-human PAECs | Group 1 | Decreases RVSP and RVHI | Inhibits apoptosis, promotes PAEC proliferation and viability | ||
Gene therapy | AAV1.hSIN3a | Increases BMPR2 | MCT-PAH rat, Su/Hx-PAH mouse | Group 1 | Decreases mPAP, and RVSP; increases CO | Inhibits PASMC proliferation and migration, attenuates pulmonary vascular remodeling and RVH | |
Il6 knockout | Increases BMPR2 | Bleomycin-PH mouse | Group 3 | Decreases RVSP | Attenuates pulmonary fibrosis, pulmonary vascular thickening, and RVH | ||
Inhba knockout | Stabilizes BMPR2 | hypoxia-PH mouse | Group 3 | Decreases RVSP | Inhibits PAEC apoptosis and improves tube information; attenuates pulmonary vascular remodeling and RVH | ||
Ctsl knockdown | Stabilizes BMPR2 | MCT-PAH and Su/Hx-PAH rat | Group 1 | Decreases RVSP | Inhibits PAEC pyroptosis, attenuates pulmonary vascular remodeling and RVH | ||
CYP2J2 overexpression | Inhibits TGF-β/Smad2 | MCT-PAH rat | Group 1 | / | Attenuates RVH | ||
Capns1 knockout | Inhibits TGF-β/Smad2 | hypoxia-PH mouse | Group 3 | Decreases RVSP and RVHI | Reduces medial thickness of the pulmonary vascular wall | ||
CPS1-IT overexpression | Inhibits HIF-1α | OSA rat | Group 3 | Decreases mRVP, mPAP | Inhibits excessive proliferation of vascular cells and inflammation | ||
HIF1A overexpression | Activates HIF-1α | PASMCs from IPAH patients | Group 1 | / | Blocks the contraction of PASMCs | ||
CMG2 overexpression | Activates PI3K/Akt | SPS-PAH rat, human PASMCs, and human PAECs with CMG2 knockdown | Group 5 | Decreases mPAP, PASP, and RVSP | Inhibits PASMC proliferation | ||
Adenovirus-mediated A20 | Inhibits NF-κB | hypoxia-PH mouse, hypoxic rat PASMCs | Group 1 | Reduces RVSP | Inhibits PASMC proliferation, attenuates pulmonary vascular remodeling and RVH | ||
Nfkbia mutant plasmid | Inhibits NF-κB | MCT-PAH rat | Group 1 | Decreases RVSP | Restores endothelial cell function by inhibiting apoptosis and reversing EndMT | ||
Nkd1 overexpression | Inhibits Wnt/β-catenin | MCT-PAH mouse, hypoxic mouse PASMCs | Group 1 | Decreases RVSP | Inhibits PASMC proliferation and migration and attenuates RVH | ||
si-circ_0016070 | Inhibits TCF4/β-catenin | MCT-PAH rat, hypoxia-PH rat | Group 1, 3 | Decreases RVSP and RVHI | Attenuates pulmonary vascular remodeling | ||
Medication | FK506 | Activates BMPR2 | PAH patients, MCT-PAH, Su/Hx-PAH rat, BMPR2 mutant PMVECs from IPAH patients | Group 1 | Decreases RVSP | Increases angiogenesis and attenuates RVH | |
Seralutinib | inhibit PDGFR, increase BMPR2 | PAH patients; Su/Hx-PAH rat, MCT-PAH rat | Group 1 | Decreases PASP and RVSP | Inhibits proliferation of PAECs, PASMCs, and lung fibroblasts, and attenuates pulmonary artery muscularization and RVH | ||
Enzastaurin | Increase FHIT/BMPR2 | Su/Hx-PAH rat; hypoxia-PH mouse with Fhit-/- or Bmpr2+/- | Group 1, 3 | Decreases RVSP | Attenuates DNA damage, decreases apoptosis, restores tube formation of PAECs, attenuates RVH, cardiac fibrosis, and vascular remodeling | ||
BMP9 | Activates BMPR2/Smad1/5 | Spontaneous PH mouse, MCT-PAH, Su/Hx-PAH rat | Group 1 | Decreases RVSP | Inhibits PAEC apoptosis, enhances monolayer integrity, and attenuates pulmonary arterial muscularization | ||
RhBMP9 | Activates BMPR2/Smad1/5/9 | Bleomycin-PH rat | Group 3 | Decreases RVSP | Inhibits PMVEC apoptosis, interstitial collagen deposition, and media thickening | ||
Soluble GP130 | Increases BMPR2 | Bleomycin-PH mouse | Group 3 | Decreases RVSP | Attenuates pulmonary fibrosis, pulmonary vascular thickening, and RVH | ||
DHEA | Activates BMPR2, inhibits RhoA/ROCK | MCT-PAH rat | Group 1 | Decreases PAP | Inhibits proliferation, increases apoptosis of PASMCs, and attenuates RVH | ||
Isorhamnetin | Activates BMPR2/Smad1/5 | MCT-PAH rat | Group 1 | Decreases mPAP, and RVSP | Prevents PAEC injury, inhibits PASMC proliferation and hypertrophy, | ||
Elafin | Stabilizes BMPR2 | Su/Hx-PAH rat, PAECs from PAH patients | Group 1 | Decreases RVSP; increases CO | Improves PAEC survival and angiogenesis, inhibits PASMC proliferation and anti-apoptosis, attenuates pulmonary vascular remodeling and RVH | ||
Follistatin | Stabilizes BMPR2 | Conditioned medium (derived from IPAH-ECs) induced PAECs | Group 1 | Decreases RVSP | Inhibits PAEC apoptosis and improves tube information; attenuates pulmonary vascular remodeling and RVH | ||
Sotatercept | Inhibits TGF-β/Smad2/3 | PAH patients, MCT-PAH, Su/Hx-PAH rat | Group 1 | Decreases PVR and RVSP | Reduces inflammation, inhibits PASMC and PMVEC proliferation, attenuates arteriolar muscularization | ||
IN-1233 | Inhibits TGF-β | MCT-PAH rat, TGF-β-rat PASMCs | Group 1 | Decreases RVSP | Inhibits PASMC migration and prevents RVH | ||
SB525334 | Inhibits TGF-β | MCT-PAH rat | Group 1 | Decreases RVP | Inhibits RVH, and reverses pulmonary artery muscularization | ||
SD-208 | Inhibits TGF-β | MCT-PAH rat | Group 1 | Decreases RVSP, RVDP and increases CO | Inhibits PASMC proliferation | ||
Aspirin | Inhibits HIF-1α/TGF-β | hypoxia-PH rat | Group 3 | / | Reduces ECM remodeling | ||
Berberine | Inhibits TGF-β | hypoxia-PH mouse | Group 3 | Decreases RVSP | Inhibits PASMC proliferation and reduces pulmonary artery muscularization | ||
Danshensu | Inhibits TGF-β | hypoxia-PH rat | Group 3 | Decreases RVSP and RVHI | Inhibits PASMC proliferation | ||
Ginsenoside Rg1 | Inhibits NF-κB/TGF-β | hypoxia-PH rat | Group 3 | Decreases RVSP and mPAP | Reduces inflammatory factors and prevents pulmonary vascular remodeling | ||
Pioglitazone | Inhibits TGF-β | LPR1-/- -IPAH mouse, PASMCs from PAH patients | Group 1 | Decreases RVSP, RVEDP, LVSP and LVEDP | Inhibits PASMC proliferation and pulmonary vascular remodeling, and reverses RVH | ||
C76 | Inhibits HIF-2α | Egln1-/- mouse, Su/Hx-PAH rat, MCT-PAH rat | Group 1 | Decreases RVSP | Attenuates pulmonary vascular remodeling | ||
PT2567 | Inhibits HIF-2α | Su/Hx-PAH rat, hypoxia-PH rat | Group 1, 3 | Decreases PVR and mPAP | Decreases inflammation, proliferation, and vascular remodeling | ||
Caffeic Acid Phenethyl Ester | Inhibits HIF-1α | MCT-PAH rat | Group 1 | Decreases RVSP | Inhibits proliferation and promotes apoptosis | ||
2-Methoxyestradiol | Inhibits HIF-1α | hypoxia-PH in OVX rat, hypoxia- human PASMCs | Group 3 | Decreases mPAP | Prevents mitochondrial ultrastructure damage and alleviates oxidative stress | ||
Digoxin | Inhibits HIF-1α | hypoxia-PH mouse | Group 3 | Decreases RVSP | Reduces pulmonary vascular remodeling | ||
Luteolin | Inhibits HIF-2α and PI3K/Akt | hypoxia-PH rat and MCT-PAH rat | Group 1, 3 | Decreases mPAP | Inhibits PASMC proliferation and migration, pulmonary fibrosis, and pulmonary vascular remodeling, improves endothelial function | ||
anti-CD146 antibody | Inhibits HIF-1α | MCT-PAH rat | Group 1 | Decreases RVSP | Attenuates pulmonary vascular remodeling | ||
Baicalin | Inhibits HIF-1α and Akt | hypoxia-PH rat | Group 3 | Decreases RVSP | Inhibits PASMC proliferation | ||
Apigenin | Inhibits HIF-1α | hypoxia-PH rat | Group 3 | Decreases RVSP | Promotes apoptosis | ||
PT2385 | Inhibits HIF -2α | Su/Hx-PAH rat | Group 1 | Decreases RVSP | Prevents PAEC apoptosis and attenuates RVH | ||
Dichloroacetate | Inhibits HIF-1α | hypoxic human PASMCs | Group 3 | / | Increases apoptosis and inhibits proliferation | ||
3PO | Inhibits ERK | MCT-PAH rats | Group 1 | Improves PAAT and CO, decreases RVSP | Improves right ventricular function, attenuates collagen synthesis and PASMC proliferation | ||
SB203580 and PH-797804 | Inhibits p38 | MCT-PAH rat, hypoxia-PH rat | Group 1, 3 | Decreases RVSP | Attenuates pulmonary vascular remodeling and RVH | ||
Astragaloside IV | Inhibits ERK | MCT-PAH rat, hypoxic human PASMCs and PAECs | Group 1, 3 | Decreases RVSP | Decreases inflammation and prevents proliferation and dysfunction | ||
Paeoniflorin | Inhibits p38/ERK | MCT-PAH rat | Group 1 | Decreases RVSP | Reduces inflammation and EndMT, and attenuates pulmonary vascular and RV remodeling | ||
GS-444217 | Inhibits p38/JNK | MCT-PAH rat, Su/Hx-PAH rat | Group 1 | Decreases mPAP | Attenuates pulmonary vascular remodeling and RVH | ||
Baicalin | Inhibits PI3K/Akt | hypoxia-PH rat | Group 3 | Decreases RVSP | Attenuates pulmonary arterial remodeling and RVH | ||
Ligustrazine | Inhibits PI3K/Akt | MCT-PAH rat | Group 1 | Decreases RVSP | Inhibits PASMC proliferation and inflammation, and attenuates pulmonary vascular remodeling and RVH | ||
3-Bromopyruvate | Inhibits PI3K/Akt | MCT-PAH rat | Group 1 | Increases TAPSE, decreases RVHI | Inhibits PASMC proliferation and pulmonary vascular remodeling, preserves mitochondrial morphology, but causes ascites and organ cirrhosis. | ||
Dacomitinib | Inhibits PI3K/Akt | MCT-PAH rat | Group 1 | Decreases RVSP | Inhibits PASMC proliferation, migration, and autophagy, reduces pulmonary vascular remodeling, and prevents RVH | ||
Spermine | Inhibits PI3K/Akt and ERK | hypoxic human PASMCs | Group 3 | / | Causes G1/G0 cell cycle arrest and inhibits PASMC proliferation | ||
NPS2390 | Inhibits PI3K/Akt | hypoxic human PASMCs | Group 3 | / | Inhibits autophagy and proliferation of PASMCs, while promoting a shift from a synthetic to a contractile phenotype | ||
Resveratrol | Inhibits PI3K/Akt and NF-κB | hypoxia-PH rat, MCT-PAH rats, hypoxic human PASMCs | Group 1, 3 | Decreases RVSP | Attenuates PASMC proliferation, and RVH | ||
Genistein | Activates PI3K/Akt | hypoxia-PH and MCT-PAH rat; hypoxic PAECs (Broiler chickens) | Group 1, 3 | Decreases PAP | Restores endothelial function, reduces RVH and increases survival rates | ||
Tanshinone IIA | Activates PI3K/Akt | MCT-PAH rat | Group 1 | Decreases PAP | Attenuates pulmonary artery remodeling | ||
17β-estradiol | Activates PI3K/Akt | MCT-PAH in OVX rat | Group 1 | Decreases RVSP, mPAP | Enhances apoptosis, reduces PASMC proliferation, and attenuates RVH | ||
Simvastatin | Inhibits NF-κB | MCT-PAH rat, PDGF-rat PVSMCs | Group 1 | Decreases mPAP | Enhances PVSMC apoptosis and reduces endomembrane proliferation in pneumono-arteriole | ||
Atorvastatin | Inhibits NF-κB | CRP-human PASMCs | Group 1 | / | Alleviates inflammation in human PASMCs. | ||
Prednisolone | Inhibits NF-κB | PDGF-human PASMCs | Group 1 | / | Exerts anti-inflammatory and antiproliferative effects on PASMCs | ||
Nicorandil | Inhibits NF-κB | hypoxic human PAECs | Group 3 | / | Inhibits PAEC apoptosis | ||
Treprostinil | Inhibits NF-κB | Inflammatory cytokines-induced human alveolar macrophages | Group 1 | / | Inhibits secretion and gene expression of inflammatory cytokines | ||
Pyrrolidine dithiocarbamate | Inhibits NF-κB | MCT-PAH rat, CRP-human PAECs | Group 1, 3 | Decreases PAP | Reduces macrophage infiltration and inflammation in PAECs, and prevents RVH | ||
IMD-0354 | Inhibits NF-κB | MCT-PAH rat | Group 1 | Decreases RVSP | Suppresses PASMC proliferation and induces PASMC apoptosis | ||
HGF | Inhibits NF-κB | MCT-PAH rat | Group 1 | Decreases mPAP and RVHI | Reduces inflammation | ||
Hydrogen sulfide | Inhibits NF-κB | MCT-PAH rat, TGF-β-human PAECs | Group 1 | Decreases RVSP | Inhibits EndMT and attenuates RVH | ||
Paeoniflorin | Inhibits NF-κB and MAPK | MCT-PAH rat, TGF-β-human PAECs, PDGF-B-human PASMCs | Group 1 | Decreases RVSP | Partially reverses EndMT, reduces right ventricular pressure and remodeling, and attenuates RVH | ||
Alginate oligosaccharides | Inhibits NF-κB and p38 | MCT-PAH rat | Group 1 | Decreases RVHI | Attenuates pulmonary arteriolar remodeling | ||
Enalapril | Inhibits NF-κB | Bleomycin-PH mouse | Group 3 | Decreases PAP | Reduces lung injury | ||
MnTE-2-PyP | Inhibits NLRP3 | hypoxia-PH mouse | Group 3 | Decreases RVSP | Decreases inflammation and attenuates vascular remodeling | ||
Jiedu Quyu Decoction | Inhibits NLRP3 | MCT-PAH rat | Group 1 | Improves PAT and CO | Mitigates right-sided heart failure associated with PAH | ||
Sulforaphane | Inhibits NLRP3 | Su/Hx-PAH mouse | Group 1 | Decreases RVHI, improves RV function | Prevents pulmonary vascular remodeling and RVH | ||
PNU-282987 | Inhibits NLRP3 | MCT-PAH rat | Group 1 | Decreases RVSP | Attenuates fibrosis, RVH, and improves survival | ||
MCC950 | Inhibits NLRP3 | MCT-PAH rat | Group 1 | / | Decreases apoptosis and inflammation | ||
Astragaloside IV | Inhibits NLRP3 | MCT-PAH rat, MCTP-human PAECs | Group 1 | / | Decreases apoptosis and inflammation in PAECs | ||
Ellagic Acid | Inhibits NLRP3 | MCT-PAH rat | Group 1 | Decreases RVSP and RVHI | Reduces oxidative stress and hypertrophy | ||
Adenoviral sJag1 transfection | Inhibits Notch1/3 | hypoxia-PH mouse, MCT-PAH rat | Group 1, 3 | Decreases mPAP and RVHI | Inhibits PASMC proliferation, enhances apoptosis, restores PASMC phenotype, improves survival rate | ||
Nitrite plus metformin | Activates AMPK | SU5416/Obese ZSF1 rat (PH-HFpEF) | Group 2 | Decreases RVSP | Attenuates hyperglycemia, glucose intolerance, and vascular remodeling | ||
Metformin | Activates AMPK | Su/Hx-PAH rat, hypoxia-PH mouse, MCT-PAH rat, Group 3 PH patients | Group 1, 3 | Decreases RVSP and RVHI | Attenuates collagen deposition, pulmonary vascular remodeling, RVH, phenylephrine-induced contractions, and endothelial function | ||
Treprostinil and metformin | Activates AMPK | Metabolic syndrome-associated PH-HFpEF mouse, SU5416/Obese ZSF1 rat | Group 2, 5 | Increases PAAT/ET and TAPSE | Attenuates hyperglycemia, and glucose intolerance and improves cardiac function | ||
Ponatinib | Inhibits Wnt5a/β-catenin | Bleomycin-PH, hypoxic human PASMCs | Group 3 | Decreases RVSP | Attenuates pulmonary vascular remodeling | ||
SBFI-26 | Inhibits Wnt/β-catenin | PH-LHD mouse | Group 2 | Decreases RVSP | Improves RV function and inhibits pulmonary vascular remodeling | ||
Doxycycline | Activates FGF2/FGFR | hypoxia-PH mouse | Group 3 | Decreases RVP | Reduces EndMT and RVH | ||
Dovitinib | Inhibits FGF2/FGFR | MCT-PAH rat | Group 1 | Decreases mPAP | Inhibits proliferation of PASMCs and Pulmonary ECs | ||
PD173074 | Inhibits FGF2/FGFR | MCT-PAH | Group 1 | Decreases mPAP, RVSP and PASP | Reduces RVH and proliferation of PASMCs | ||
Rosiglitazone | Activates PPARγ | SMYD2 overexpression in hypoxia-PH mouse and PASMCs | Group 3 | Decreases RVSP | Decreases PASMC proliferation and attenuates RVH, and pulmonary vascular remodeling | ||
Sildenafil | Activates PPARγ | hypoxia-PH rat, hypoxic human PASMCs | Group 3 | Decreases RV mean pressure | Inhibits proliferation and attenuates RVH | ||
Canagliflozin | Activates PPARγ | hypoxia-PH mouse, Su/Hx-PAH mouse and rat, MCT-PAH rat | Group 1, 3 | Decreases RVSP, PAT, and PAT/PET | Inhibits excessive oxidative stress and proliferation, and attenuates pulmonary vascular remodeling | ||
Fasudil | Inhibits RhoA/ROCK | hypoxia-PH rat | Group 3 | Decreases mPAP and RVSP | Decreases the migration of human PMVECs and attenuates pulmonary vascular remodeling | ||
KMUP-1 | Inhibits RhoA/ROCK | U46619-PAH, MCT-PAH rat | Group 1 | Decreases mPAP | Decreases vascular remodeling and vasoconstriction | ||
G1 | Activates GPER | MCT-PAH rat | Group 1 | Decreases LVCO, RVCO, and RVSP | Promotes pulmonary endothelial NO synthesis, Ca2+ handling regulation, reduces inflammation in CMs, and collagen deposition | ||
NPS2143 | Inhibits CaSR | MCT-PAH rat, hypoxia-PH mouse | Group 1, 3 | Decreases RVSP | Attenuates myocardial fibrosis and RVH | ||
Docosahexaenoic acid | Inhibits CaSR | hypoxia-PASMCs | Group 1 | / | Reduces the proliferation and migration of PASMCs | ||
Chloroquine | Inhibits CaSR | hypoxia-PH rat | Group 3 | / | Attenuate arteriole thickness | ||
NPS2143/sildenafil | Inhibits CaSR | IPAH-PASMCs | Group 1 | / | Reduces proliferation of PASMCs | ||
Vitamin K3, MG-132 | Inhibits Hippo | MCT-PAH rat | Group 1 | Decreases RVSP, RVHI | Decreases PASMC proliferation and anti-apoptosis, alleviates pulmonary arterial remodeling | ||
Cinnamaldehyde | Inhibits cGAS-STING | MCT-PAH rat | Group 1 | Decreases RVOT, increases PATET | Decreases PASMC proliferation and inflammatory responses, alleviates mitochondrial damage and vascular remodeling | ||
SITO | Inhibits cGAS-STING | MCT-PAH rat | Group 1 | Decreases RVSP | Inhibits proliferation and promotes apoptosis of PASMCs, mitigates phenotypic switching | ||
