semaxanib (SU5416) / Pfizer - LARVOL DELTA

Pharmacological Profile and Therapeutic Evaluation of ROC-101, a Potent and Selective ROCK Inhibitor, in Arterial Hypertension and Pulmonary Fibrosis. (PubMed, Pharmacol Res) - "Herein, we present a novel selective inhibitor of ROCK1 and ROCK2 (pan-ROCK), ROC-101 (previously known as KD045), and demonstrate its activity as an antifibrotic agent. ROC-101 was efficacious in three different rodent models of pulmonary parenchymal, vascular, and airway diseases: 1) ROC-101 treatment reduced airway hypersensitivity to methacholine in an ovalbumin-induced asthma model and had blood pressure-lowering effects consistent with the role of ROCK in smooth muscle contractility and confirming in vivo target engagement; 2) ROC-101 showed efficacy in attenuating pulmonary arterial hypertension in the semaxanib/hypoxia-induced disease model; and 3) in the bleomycin-induced lung fibrosis model, ROC-101 demonstrated disease-modifying activity in the fibrotic lung, lowering collagen deposition, improving histology, reducing immune cell infiltration, and decreasing ROCK target phosphorylation. These in vivo and functional assessments support the development of..."

Journal • Asthma • Cardiovascular • Fibrosis • Hypertension • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CTGF

The sodium-glucose co-transporter 2 inhibitor, empagliflozin, attenuates pulmonary vascular remodelling by inhibiting the phosphorylation of PDGF receptor-β. (PubMed, Br J Pharmacol) - "The results highlight a novel mechanism underlying the beneficial effects of empagliflozin in PAH, through direct binding to the tyrosine kinase effector domain of PDGFRβ. This interaction inhibits PDGFRβ phosphorylation, offering new insights into therapeutic strategies for PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • PDGFRB

Agomelatine alleviates hypoxia-induced pulmonary arterial hypertension by activating mitophagy via the SIRT1/FoxO1/ULK1 signaling pathway. (PubMed, Biochem Pharmacol) - "The present investigation was designed to evaluate the ameliorative potential of AGM on pulmonary vascular remodeling in a SU5416/hypoxia (SuHx)-induced PAH rat model, and to elucidate the concomitant mechanistic pathways. In contrast, inhibition of SIRT1 resulted in increased FoxO1 acetylation, which subsequently downregulated ULK1 expression and impaired mitophagy. Collectively, these findings establish that AGM exerts therapeutic effects in PAH by enhancing ULK1-dependent mitophagy through modulation of the SIRT1/FoxO1 signaling axis, underscoring its potential as a novel therapeutic candidate for PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Nitazoxanide reverses pulmonary vascular remodeling in pulmonary hypertension by targeting the IMPA1-RAGE signaling axis. (PubMed, Toxicol Appl Pharmacol) - "Nitazoxanide, an FDA-approved antiparasitic agent with favorable safety and bioavailability, significantly reduced PAP and alleviated pulmonary vascular remodeling in experimental models of PH, including the SU5416/hypoxia and monocrotaline rat models. Mechanistically, nitazoxanide treatment inhibited the IMPA1-RAGE interaction, thereby suppressing downstream activation of the PI3K/Akt/mTOR signaling cascade and attenuating the enhanced glycolysis characteristic of PASMCs in PH. Collectively, our findings highlight nitazoxanide as a promising therapeutic candidate for pulmonary vascular remodeling and pulmonary hypertension."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Lactate dehydrogenase-induced DNA Topoisomerase 1 is a novel regulator of smooth muscle cell proliferation and remodeling in pulmonary arterial hypertension. (PubMed, bioRxiv) - "By using lung tissues and pulmonary vascular cells from PAH and non-diseased human lungs, unbiased proteomics, network analysis, and gain-and-loss of function approaches, we here report that up-regulation of lactate dehydrogenase A (LDHA)-lactate axis promotes PASMC-specific over-lactylation and consequent over-accumulation of DNA topoisomerase 1 (TOP1) in small remodeled PAs from PAH lungs, leading to the up-regulation of Akt-mechanistic target of rapamycin 1 (mTORC1) signaling, hyper-proliferation, and reduced apoptosis. Smooth muscle-specific LDHA knockdown prevented, and Ldha inhibitor oxamate reversed SU5416/hypoxia-induced TOP1 accumulation, pulmonary vascular remodeling, and pulmonary hypertension (PH) in mice...Collectively, these data provide a novel mechanistic link from LDHA-driven lactate over-production through lactylation and overaccumulation of TOP1, to the up-regulation of Akt-mTORC1, hyper-proliferation and apoptosis resistance of PASMCs, pulmonary..."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • LDHA • TOP1

NADPH Oxidase (NOX) Activity in a Rat Model of Emphysema with Pulmonary Hypertension Induced by SU5416/Hypoxia (APSR 2025) - "Conclusion : Administration of the VEGFR inhibitor SU5416 under hypoxic conditions induced emphysema and pulmonary hypertension in rats. The upregulation and interaction of VEGFR2 and NOX4 may contribute to the molecular mechanisms underlying hypoxia-induced pulmonary hypertension in this rat model."

Preclinical • Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • KDR • NOX4

Biased small molecule RXFP1 agonists ameliorate experimental pulmonary hypertension and RV hypertrophy (AHA 2025) - "Serum and PDGF-BB-induced migration of PASMC were inhibited by RLN2, ML290 and derivatives. Humanized RXFP1 knock-in (hRXFP1-KI) mice subjected to SU5416 and hypoxia (FiO2=0.1) for three weeks and treated with ML290, TRND8394, AZD5462 (10 mg/kg/d p.o.), or ACTRIIA-Fc (a.k.a., sotatercept, 2.2 mg/kg/twice weekly i.p.) had comparable improvements in right ventricular systolic pressure (RVSP) vs. disease controls, while treatment with biased compounds ML290 and TRND8394, and ACTRIIA-Fc elicited potent decreases in RV hypertrophy (RV/LV+S).ConclusionSmall molecule RXFP1 agonists with biased GPCR signaling may elicit more potent effects in experimental PH upon right ventricular hypertrophy than non-biased RXFP1 agonists and represent a promising therapeutic strategy for cardiopulmonary disease."

Cardiovascular • Congestive Heart Failure • Heart Failure • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • CALD

NEDD9 Inhibition Reverses Fibrotic Remodeling In Experimental Pulmonary Arterial Hypertension (AHA 2025) - "In addition, all those values were significantly improved compared to SU-5416-Hyp-Norm rats at day 14.Conclusion NEDD9 inhibition reversed fibroproliferative remodeling in SU-5416-Hyp-Norm model of PAH. These results suggest NEDD9 is a potential therapeutic target by which to modulate sustained improvement in pulmonary hypertension."

Cardiovascular • Fibrosis • Pulmonary Arterial Hypertension • Respiratory Diseases • NEDD9

Fenofibrate as a Modulator of the Renin-Angiotensin System in Su/Hx-Induced Pulmonary Arterial Hypertension. (PubMed, Int J Mol Sci) - "We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin-angiotensin system (RAS). In the RV, Ang-(1-7) increased, ACE2 was preserved, and NO2- and NO3 levels were maintained. FF exerts protective effects in Su/Hx-induced PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • RAS

TRIB2 Promotes Pulmonary Artery Smooth Muscle Cell Proliferation through SERCA2 Ubiquitination in Pulmonary Hypertension. (PubMed, Free Radic Biol Med) - "Using platelet-derived growth factor-BB (PDGF-BB)-stimulated primary human PASMCs, hypoxia/Su5416-induced PH mice, and monocrotaline-treated PH rat models, we demonstrated elevated TRIB2 levels in both rodent PH models and PDGF-BB-stimulated PASMCs...Furthermore, in vivo, Trib2 knockdown significantly ameliorated PVR and pulmonary hemodynamics in PH rats. Our findings demonstrate that TRIB2 contributes to PASMC hyperproliferation through SERCA2 ubiquitination in PH, highlighting TRIB2 as a potential therapeutic target for PH treatment."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • ERN1 • SMURF1 • UBR5 • XBP1

HIF1α/PRDX1 axis drives pulmonary vascular remodeling through DRP1 DeSUMOylation and mitochondrial fragmentation. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In vivo, endothelial-specific PRDX1 knockdown in a hypoxia/SU5416(SuHx)-induced PH rat model significantly reduced right ventricular systolic pressure, vascular wall thickening, and endothelial hyperproliferation, while improving exercise tolerance. These findings reveal a novel HIF1α-PRDX1-DRP1 axis driving mitochondrial fragmentation and vascular remodeling in PH, positioning PRDX1 as a promising therapeutic target for halting disease progression."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • HIF1A • PRDX1 • SENP3

The Role and Mechanism of Add3-mediated Pulmonary Artery Smooth Muscle Cell Transformation in Pulmonary Arterial Hypertension (AHA 2025) - "Western blot analysis confirmed that Add3 protein levels were significantly higher in PAH HPASMCs than in normal controls (Figure), consistent with the single-cell sequencing results.For in vivo experiments, we generated Add3-/- mice and subjected them to Su/Hx (Su5416/Hypoxia) at 8-10 weeks of age. After one month, right heart catheterization, echocardiography, and hematoxylin-eosin (HE) staining of lung tissue sections were performed. The results demonstrated that Add3 knockout delayed PAH progression in mice (Figure 2).This study reveals that Add3 is able to promote the progression of PAH, which provides a new target for intervention in the treatment of PAH."

Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

Knockout of the cytosolic RNA receptor melanoma differentiation-associated protein 5 reduces pulmonary hypertension (AHA 2025) - "Ifih1-/- mice were exposed to the hypoxia/SU5416 (HX/Su) protocol for 21 days... Our data suggest a protective effect of whole-body MDA5 knockout in mice, which may be due to a reduction in pro-inflammatory mediators and perivascular immune cell accumulation. Whether a decrease of MDA5 in ECs promotes or protects against PH will need further investigation."

Cardiovascular • Hypertension • Melanoma • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Solid Tumor • IFIH1 • ITGAM

Protein Arginine Methyltransferase 5 Drives Pulmonary Arterial Remodeling in Pulmonary Arterial Hypertension (AHA 2025) - "However, the role of PRMT5 and its potential interplay with lactate in PAH remains unknown.Goal: To determine the role of PRMT5 in PA remodeling and PAH. Immunohistochemical, immunoblot, proteomic analyses, proliferation, apoptosis assays; SU5416/Hypoxia (SuHx) mouse and rat models of PH. PRMT5 was over-accumulated in SMα-actin-positive areas of small muscular PAs from PAH patients and rats with SuHx PH, and distal human PAH PASMCs compared to non-diseased controls, supporting increased protein SDMA modification, PASMC hyper-proliferation, and apoptosis resistance. Collectively, our data suggest that LDHA/lactate and PDGF-BB-driven PRMT5 up-regulation promotes PASMC hyper-proliferation, survival, PA remodeling, and PH via activating Akt/mTOR. Targeting PRMT5 signaling could represent potentially attractive strategy to treat PAH."

Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases • LDHA • PRMT5

A Novel tRNA-Derived Small RNA, tRF-1:32-Glu-TTC-2-M2, Regulates Right Ventricular Remodeling and Fibrosis by Targeting P4HA2 in Pulmonary Arterial Hypertension (AHA 2025) - "We performed high-throughput sequencing to profile tsRNA expression in plasma from PAH patients and RV tissues from monocrotaline (MCT) rats and established two rat models of PAH (MCT and SU5416 combined with hypoxia)...Our findings reveal a novel tsRNA-mediated regulatory axis in PAH-associated RV fibrosis, where tRF-1:32-Glu-TTC-2-M2 attenuates maladaptive remodeling through inhibition of P4HA2. This study identifies tRF-1:32-Glu-TTC-2-M2 as both a promising therapeutic target and biomarker for PAH, paving the way for RV-directed precision medicine strategies."

Cardiovascular • Fibrosis • Immunology • Pulmonary Arterial Hypertension • Respiratory Diseases

Pathological mechanisms of Down syndrome-associate pulmonary arterial hypertension (AHA 2025) - "We exposed Ts1Cje mice to chronic hypoxia for three weeks, followed by one week of normoxia after SU5416 injection. Our findings confirm that the DYRK1A/PPARG/EGR1 pathway plays a central role in the pathogenesis of PAH in a DS mouse model. Pioglitazone may represent a promising therapeutic agent for DS-associated PAH."

Cardiovascular • Developmental Disorders • Genetic Disorders • Pulmonary Arterial Hypertension • Respiratory Diseases • CASP3 • EGR1 • PPARG

3CPR Best Abstract Award: The pathogenic role of ADAMTS13 deficiency in Chronic Thromboembolic Pulmonary Hypertension (AHA 2025) - "Previous reports have indicated that patients with CTEPH exhibit decreased plasma ADAMTS13 levels and elevated VWF levels, but the precise mechanism and extent of its involvement remain unclear.Aims: This study aimed to investigate the role of the ADAMTS13-VWF axis in the pathogenesis of CTEPH. A novel rat CTEPH model was established in wild-type and ADAMTS13-knockout Sprague Dawley (SD) rats through repeated autologous thrombus injections with a single administration of the vascular endothelial growth factor receptor inhibitor, SU5416... Our findings indicate the successful establishment of a novel rat CTEPH model that replicates key hemodynamic and pathological features of human CTEPH. This study is the first in vivo investigation of the ADAMTS13–VWF axis in CTEPH and holds strong potential to transform clinical management and improve outcomes for patients with CTEPH and related pulmonary hypertension."

Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases

Comprehensive chemical analysis of polyphenols in the ethyl acetate extract from the roots of Ephedra sinica Stapf and evaluation of its therapeutic effects on SU5416/hypoxia-induced pulmonary arterial hypertension rats. (PubMed, Bioresour Bioprocess) - "Meanwhile, ERE improved gut microbial dysbiosis and the disturbed glycerophospholipid metabolism. Collectively, this study presents the first report on the efficacy of A-type PACs from Ephedra sinica for the treatment of PH through regulating gut microbiota and host metabolism."

Journal • Preclinical • Cardiovascular • Hypertension • Metabolic Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

THE IMPACT OF PLATELET-DERIVED GROWTH FACTOR-BB ANTAGONIST ANTIBODY ON RIGHT HEART FAILURE IN PULMONARY HYPERTENSION IN PRECLINICAL ANIMAL STUDIES (CHEST 2025) - "We employed an investigational fully human monoclonal antibody, REGN13335, which is designed to bind and neutralize PDGF-B with high affinity, to evaluate its therapeutic potential in mitigating RV remodeling and dysfunction using echocardiography and cardiac magnetic resonance imaging (MRI) in the SU5416/hypoxia (SuHx) PAH rat model. Longitudinal RV imaging by echocardiography and MRI effectively detected RV remodeling and dysfunction in the SuHx rat model of PAH. REGN13335 treatment mitigated RV remodeling, preserved RV function, and improved oxygen saturation. CLINICAL IMPLICATIONS: Targeting the PDGF-BB pathway with REGN13335 may offer a novel therapeutic strategy to prevent or reverse RV remodeling and dysfunction in PAH patients."

Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • GDF15 • MYH7 • PDGFRB

Targeted delivery of BMPR2 mRNA attenuates pulmonary arterial hypertension by reversing pulmonary vascular remodeling. (PubMed, Acta Pharm Sin B) - "Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling...Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Mechanistic study of ANXA3-mediated endoplasmic reticulum stress promoting M1 macrophage polarization in pulmonary arterial hypertension based on bioinformatics and nine machine learning algorithms. (PubMed, Comput Biol Med) - "This study demonstrates that ANXA3 regulates ERS to drive M1 macrophage polarization and inflammation, which subsequently promotes PASMC function and promotes PAH progression. ANXA3 may serve as a novel immunoinflammatory target and potential therapeutic candidate."

IO biomarker • Journal • Cardiovascular • Hypertension • Immune Modulation • Immunology • Inflammation • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ANXA3 • ATF4 • BCL2 • BCL2L1 • CD68 • DNAJB1 • HSPA5 • IL18 • IL1B • IL6 • TCF4 • TNFA • TNFRSF17

Cobalt Chloride-Induced Tissue Regeneration and Wound Healing Depend on HIF-1α and VEGF-A-Mediated Neovascularization. (PubMed, Zebrafish) - "To verify the role of VEGF in CoCl2-mediated tissue regeneration, the amputated fins were exposed to inhibitors such as genistein and SU5416. These results suggest that CoCl2 promotes tissue regrowth and wound healing by stimulating angiogenesis. The findings highlight the therapeutic potential of CoCl2 in enhancing regeneration and wound repair through the HIF-1α/VEGF signaling pathway, with potential implications for treating ischemic wounds."

Journal • HIF1A • VEGFA

EP4/ANXA2 axis in pulmonary arterial hypertension: therapeutic implications. (PubMed, Eur Heart J) - "This study reveals a crucial pathway involving EP4 and ANXA2 in PAH development and progression. Targeting EP4 and its downstream effector ANXA2 represents promising therapeutic strategies for PAH management."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ANXA2

miR-140-3p Alleviates Pulmonary Arterial Smooth Muscle Cell Dysfunction via MAP2K6/p38 Pathway. (PubMed, J Biochem Mol Toxicol) - "In this study, we showed that the expressions of miR-140-3p in SU5416/hypoxia (SuHx)-induced PAH and hypoxia-treated human PASMCs were significantly downregulated...Moreover, upregulation of MAP2K6 counteracted the inhibitory effect of miR-140-3p on matrix metalloproteinase 2/9 (MMP2/9) expression and pro-apoptotic effects as indicated by Bcl2/BAX in hypoxia-treated human PASMCs. Collectively, our findings highlighted the therapeutic potential of miR-140-3p in PAH and revealed a regulatory mechanism involving the miR-140-3p/MAP2K6/p38 axis."

IO biomarker • Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • BCL2 • MAP2K6 • MIR140 • MMP2 • MMP9

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase Suppresses Glycolysis and Proliferation of Pulmonary Artery Smooth Muscle Cells in Hypoxic Pulmonary Hypertension via Inhibition of lactate dehydrogenase A. (PubMed, Eur J Pharmacol) - "This study emphasizes the METTL3/LHPP/LDHA axis's role in enhancing PASMC proliferation and HPH. LHPP may represent a potential therapeutic target for the treatment of hypoxic pulmonary hypertension."

Journal • Cardiovascular • Hypertension • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • LDHA • METTL3