semaxanib (SU5416) / Pfizer - LARVOL DELTA

Enhanced Mitochondrial Mrs2-Mg2+ Signaling Drives Mitochondrial Dysfunction in Pulmonary Arterial Hypertension Rats. (PubMed, Hypertension) - "Primary pulmonary arterial smooth muscle cells isolated from monocrotaline-induced PAH rats were used for mechanistic investigation, with key metabolic and mitochondrial alterations validated in the Su5416 (semaxanib)/hypoxia model...Aberrant Mrs2-mediated mMg2+ signaling disrupts global ionic and metabolic homeostasis, driving mitochondrial dysfunction and pathogenic remodeling in PAH. Targeting the Mrs2-centered ionic-metabolic-dynamic axis may represent a potential therapeutic approach that warrants further investigation to interrupt PAH progression."

Journal • Preclinical • Cardiovascular • Hypertension • Metabolic Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • HIF1A • PKM • SLC41A3 • TRPC3

TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6. (PubMed, Free Radic Biol Med) - "Vascular smooth muscle-specific TG2 knockout (TG2VSMCKO) mice significantly ameliorated hypoxia+SU5416 and HPH...Our findings provide a strong molecular explanation for the association between TG2, mitochondrial function, and HPH. This study identified a novel target for the treatment of HPH."

Journal • Cardiovascular • Hypertension • Metabolic Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • TGM2 • TRPC6

The Sigma-1 receptor agonist PRE084 improves cardiopulmonary function and remodelling in an experimental model of pulmonary arterial hypertension. (PubMed, Biomed Pharmacother) - "Herein, we evaluated the therapeutic potential of the S1R agonist PRE084 in the hypoxia plus SU5416 (Hpx/Su) rat model of severe PAH...In summary, PRE084 markedly improved both the functional and morphological parameters characteristic of PAH, thereby attenuating disease progression. Collectively, our study suggests that targeting S1R may represent a promising therapeutic approach for the treatment of PAH."

Journal • Cardiovascular • CNS Disorders • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Linking preclinical models to clinical realities: VEGF/VEGFR inhibitors and thrombotic microangiopathy in cancer therapy. (PubMed, IMetaOmics) - "Notably, Bevacizumab, Sunitinib, Ramucirumab, and Aflibercept significantly increase TMA risks, with Bevacizumab showing the highest risk (reporting odds ratio 4.96 [4.08-6.03] in Vigibase and 2.33 [1.84-2.94] in FAERS)...Animal studies highlighted that Semaxanib causes more severe endothelial damage and thrombus formation than Bevacizumab, further validating that VEGFi typically induces TMA later than VEGFRi. Transcriptomic analysis and pan-cancer pathway insights identified critical pathways involving reduced VEGF signaling, abnormal complement activation, and excessive platelet aggregation leading to thrombosis. The results underscore the enhanced risk of TMA posed by these inhibitors, particularly noting the timelines and mechanisms through which different inhibitors trigger TMA, and recommend regular monitoring of biochemical markers for early risk assessment and management."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenic Purpura • Thrombosis

SEX DIFFERENCES IN EFFECTS OF HIGH INTENSITY EXERCISE ON RIGHT VENTRICULAR BIOMECHANICS IN EXPERIMENTAL PULMONARY HYPERTENSION (WRMC 2026) - "PH was induced through injection of Sugen (SU5416, inhibitor of vascular endothelial growth factor (VEGF)) followed by whole body hypoxia for 3 weeks, with additional 3 weeks of normoxia (SuHx)... HIIT did not reduce RV fibrosis or stiffness in male or female animals with SuHX-PH, but worsened cardiac index in females only. These findings suggest that in this model of severe PH, the RV is vulnerable to decompensation, and additional hemodynamic stress from high-intensity exercise may exacerbate dysfunction rather than conferring benefit. A future direction involves evaluating HIIT in healthy controls to establish the intrinsic RV effects of exercise independent of PH severity."

Anesthesia • Cardiovascular • Fibrosis • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Rare Diseases • Respiratory Diseases

Sine oculis homeobox 1 drives endothelial dysfunction in preclinical pulmonary arterial hypertension. (PubMed, Sci Transl Med) - "Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)-induced PH mice...Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity...Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development."

Journal • Preclinical • Cardiovascular • Hypertension • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EDN1 • MAPK1 • MAST4 • SIX1

Deciphering the Counterintuitive Role of Vascular Endothelial Growth Factor Signaling Pathways in Pulmonary Arterial Hypertension. (PubMed, Int J Mol Sci) - "The multifaced properties of VEGF, whether angiogenic or nonangiogenic, vary depending on the nature of the ligand, receptor-dependent and -independent signaling pathways, and the duration of the ligand-receptor engagement. Further investigation is needed to translate the knowledge acquired to human subjects and to confirm the pathogenic mechanisms surrounding the phenotypic shift to apoptosis-resistant, hyperproliferative cellular subset and the development of angio-obliterative lesions in PAH."

Journal • Review • Cardiovascular • CNS Disorders • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Large extracellular vesicles regulate endothelial angiogenic potential via paracrine and autocrine signaling. (PubMed, J Biol Chem) - "Despite advancements in anti-angiogenic cancer therapies, such as bevacizumab, late-stage tumors, including advanced melanomas, exhibit mixed clinical responses...This L-EV-mediated increase in endothelial tube formation is sensitive to the effects of sorafenib, a multi-kinase inhibitor, but not SU5416, a selective VEGF-receptor inhibitor...Finally, we show that EV subtypes have distinct effects on the acquisition of angiogenic phenotypes and their roles vary with tumor type. These findings provide new insight into the mechanisms of angiogenic therapy resistance in melanoma and demonstrate the differential functions of EV subtypes in angiogenesis across tumor types."

Journal • Melanoma • Oncology • Solid Tumor • CXCL8

Development and Characterization of a Novel Chronic Thromboembolic Pulmonary Hypertension Rat Model: Identifying Sell-Podxl as Potential Regulators. (PubMed, Hypertension) - "Male Sprague-Dawley rats were injected with gelatin sponge combined with SU5416 as a secondary insult...Our new model recapitulates human chronic thromboembolic pulmonary hypertension pathophysiology and is useful for understanding pulmonary microvasculopathy. Sell-Podxl is a previously unrecognized link between inflammation and vascular remodeling, offering a potential therapeutic target."

Journal • Preclinical • Cardiovascular • Hypertension • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • EGR1 • HIF1A • PODXL • SELP • STAT3

Paeoniflorin Alleviates Pulmonary Arterial Hypertension by Suppressing TRIM24-Mediated SIRT1 Ubiquitination and NLRP3 Inflammasome Activation. (PubMed, Chem Biol Drug Des) - "A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx)...PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis."

Journal • Cardiovascular • Hypertension • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • IL1B • IL6 • NLRP3 • SIRT1 • TNFA • TRIM24

Gut Microbiota in Pulmonary Arterial Hypertension: Murine Models and Human Microbial Signatures, Pathogenic Mechanisms, and Emerging Therapeutic Avenues. (PubMed, Compr Physiol) - "This review systematically compares gut microbiota and metabolites across PAH murine models (including chronic hypoxia, SU5416/hypoxia [SuHx], monocrotaline [MCT], and non-classical models) and patients (adults and children)...It is also discussed how the microbiota and their metabolites may influence inflammation around the pulmonary vasculature. Furthermore, the potential of probiotic therapy, fecal microbiota transplantation (FMT), and mesenchymal stem cells (MSCs) therapies as novel treatment strategies for PAH is discussed."

Journal • Preclinical • Review • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Transplantation

Differential Impact of Recruited and Resident Macrophages on Hypoxia-Induced Pulmonary Hypertension. (PubMed, Circ Res) - "Simultaneously targeting Prrx2 and Hic1 in macrophages significantly alleviated SU5416/hypoxia-induced PH in rats. The differential roles of pulmonary resMФs and recMФs in pulmonary vascular remodeling highlight novel therapeutic targets for pulmonary arterial hypertension treatment, specifically through inhibition of Hic1 and Prrx2 in macrophages."

Journal • Bone Marrow Transplantation • Cardiovascular • Fibrosis • Hematological Malignancies • Hypertension • Immunology • Infectious Disease • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • Transplantation • HIC1 • PRRX2 • SIRT1

Baicalin attenuates pulmonary hypertension by targeting AMPK/CPT1A-mediated fatty acid metabolism. (PubMed, Phytomedicine) - "This study demonstrates that baicalin alleviates PH by modulating FAO through inhibition of the AMPK/CPT1A axis. Our findings provide evidence for the therapeutic efficacy of baicalin and elucidate its molecular mechanism, suggesting a promising therapeutic intervention for PH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • AMPK • CPT1A

Large extracellular vesicles regulate endothelial angiogenic potential via paracrine and autocrine signaling. (PubMed, bioRxiv) - "Despite advancements in anti-angiogenic cancer therapies, such as bevacizumab, late-stage tumors, including advanced melanomas, exhibit mixed clinical responses...This L-EV-mediated increase in endothelial tube formation is sensitive to the effects of sorafenib, a multi-kinase inhibitor, but not SU5416, a selective VEGF-receptor inhibitor...Finally, we show that EV subtypes have distinct effects on the acquisition of angiogenic phenotypes and their roles vary with tumor type. These findings provide new insight into the mechanisms of angiogenic therapy resistance in melanoma and demonstrate the differential functions of EV subtypes in angiogenesis across tumor types."

Journal • Melanoma • Oncology • Solid Tumor • CXCL8

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