Endothelin Receptor Research Articles

The role of angiotensin II and endothelin receptor antibodies in COVID19 patients with HFpEF

Abstract Background The infection caused by the coronavirus SARS-COV-2, is associated with an unusual pattern of organ damage in comparison to other viral-induced pathologies. A theory of autoimmunity induced by ACE-2/SARS-COV-2 spike protein complex or its degradation products, was proposed as a possible explanation for the versatile and multiorgan damage in COVID-19. Aim The aim of the study is to determine whether antibodies against angiotensin II receptor type 1 (AT1R) or endothelin-1 receptor type A (ETAR) do exist in plasma of COVID -19 patients with heart failure with preserved ejection fraction and whether they correlate to the severity of the disease. Methods A total of 61 patients with COVID-19 and heart failure with preserved ejection fraction and 48 controls (free of COVID19) with heart failure with preserved ejection fraction were included. Patients were divided into two groups: patients with severe disease (admitted at the intensive care (n=30)), patients with milder clinical presentation that remained in the general therapeutical department (n=31). The plasma levels of IL-6 and auto-antibodies against AT1R or ETAR in peripheral blood were measured and compared between COVID19 patients with severe and milder disease and age matched controls. Clinical and standard laboratory parameters were also collected and their association with the research biomarkers was analysed. Results Auto-antibodies against AT1R were significantly increased in severe disease course (median 19.60 U/mL, IQR 4.8-34.75) compared to milder disease (median 10.95 U/mL, IQR 7.69 – 17.67, p=0.017) and the control group (median 6.79 U/mL, IQR 5.10 – 14.05, p< 0.001). ETAR antibody titers were also significantly increased in severe disease (median 14.52, IQR 6.76-32.94), compared to milder disease course (median 8.73 U/mL, IQR 6.59 –13.45, p=0.023) and to the control group (median 6.64, IQR 6.79 – 17.92, p <0.001). The same was the trend regarding IL-6 antibodies. Severe disease (median 12.11 U/mL, IQR 5.59–19.38); milder disease disease (median 8.64U/mL, IQR 1.84 – 14.13, p=0.039); control group (median 4.28U/mL, IQR 0.11–1.43, p<0.001).Both AT1R and ETAR correlated to IL-6 plasma levels. The results did not show association with the concomitant therapy. Conclusion In conclusion, we establishеd the presence of AT1R and ETAR autoantibodies in COVID-19 patients with heart failure with preserved ejection fraction. They correlated to IL-6 plasma levels (systemic inflammation) and are associated with severe form of the disease.

Ambrisentan reverses the prosenescent and anti-autophagic effect of high glucose on human pulmonary artery endothelial cells exposed to hypoxia

Abstract Background Cardiovascular (CV) comorbidities (systemic hypertension, hyperlipidemia, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease) are associated with reduced treatment response to specific drugs for group 1 pulmonary arterial hypertension (PAH). Often this epidemiological evidence is the result of misdiagnosis of group 2 PH associated with left heart disease, but it can also be explained as the intrinsic loss of the ability of pulmonary endothelial cells to respond to specific antiremodeling drugs. Aims To evaluate the impact of high glucose and hyperosmolar stress on the responsiveness of human pulmonary artery endothelial cells (hPAECs) to the endothelin receptor antagonist ambrisentan in terms of senescence, autophagic activity, viability and expression of some microRNAs involved in pulmonary arterial remodeling. Methods We incubated hPAECs with high glucose (HG, 30.5 mM) or high mannitol (HM, 25 mM), with/without ambrisentan (0.02 nM) in normoxia (N) or hypoxia (H) for 24 h and tested them for cell viability (MTT assay), protein and miRNA levels, autophagy and senescence (β-Gal assay) in vitro. Results H induced cell death as compared to N (752 ± 44 vs 701 ± 45 Abs units, p = 0.03). H reduced autophagy (Figure 1A-C) and induced senescence (Figure 1D), an effect further potentiated by HG and HM. Treatment with A in N and H significantly reversed the effect of HG but not HM on autophagy (Figure 1A-C) and senescence (Figure 1D). H increased the abundance of antiapoptotic miR124-3, compared to N in vehicle (V)-treated hPAEC (p=0.008) (Figure 2A), and induced a similar effect on antiapoptotic and proliferative miR191-3p, although not statistically significant (Figure 2B). In N, A potentiated the expression of both miR124-3p (p=0.007) and miR191-3p (p=0.02) in HG-treated hPAEC, and only miR191-3p in HM-treated hPAEC (p=0.01). A induced a similar effect on miR191-3p in hPAEC exposed to H+HG (p=0.02), with a non-statistically significant trend on miR124-3p. Conclusions In hPAEC exposed to H, A retains its pro-autophagic and antisenescent effects in an in vitro model mimicking diabetes. miR124-3p and miR191-3p may act as biomarkers of disease and treatment response to specific drugs in patients with PAH.Figure 1:autophagy and senescenceFigure 2:miRNA expression

Efficacy of specific drug class therapy in pulmonary arterial hypertension associated with HIV, portal hypertension or both: a single Center experience

Abstract Background Pulmonary arterial hypertension (PAH) is a rare complication of both HIV infection (HIV-PAH) and portal hypertension (Po-PAH); it can occur in patients with both diseases (HIV/Po-PAH). The use of the PAH-specific drug classes (prostanoids, endothelin-1 receptor antagonists [ERA] and phosphodiesterase-5 inhibitors [PDE5-i]) is largely justified by retrospective and observational case reports since, to date, there are no randomized clinical trials except for the PORTICO trial which demonstrated the efficacy of macitentan in Po-PAH. Purpose the aim of the study was to evaluate the efficacy of PAH-specific drugs, both monotherapy and dual oral upfront therapy (ERA + PDE5i started within 1 month apart), in patients with Po-PAH, HIV/Po-PAH and HIV-PAH. Methods Between 1998 and 2023 we enrolled patients with Po-PAH, HIV-PAH and HIV/Po-PAH referred to our Center and undergoing monotherapy with prostanoid, ERA and PDE5-I or dual upfront oral therapy. The efficacy of the drugs was assessed by comparing clinical parameters (NYHA functional class), exercise capacity (six-minute walking test) and hemodynamic parameters at baseline and after a treatment period of 3-6 months. The data are expressed as mean and standard deviation and were compared with Student's t-test for paired data. Results 128 patients were enrolled (83 Po-PAH, 23 HIV/Po-PAH and 22 HIV-PAH). 20 were treated with ERA monotherapy, 90 with PDE5-I, 13 with prostanoids and 5 treated with dual oral upfront therapy. Conclusions Prostanoids, ERAs and PDE5-Is, both in monotherapy and as dual upfront oral therapy, are associated with a significant improvement in functional class, exercise capacity and hemodynamic parameters. The effect of such drugs is similar to patients suffering from other forms of PAH.

Angiotensin-II receptor type 1 and endothelin-1 receptor type A agonistic autoantibodies in patients with STEMI: new kids on the block

Abstract Background The Prognosis after ST-elevation myocardial infarction (STEMI) remains poor. Angiotensin-II and endothelin-1 contribute to adverse prognosis after STEMI through molecular mechanisms that lead to myocardial inflammation, fibrosis and, ultimately, adverse myocardial remodeling. Functional autoantibodies against angiotensin II type 1 (AT1R-AAs) and endothelin-1 type A (ETAR-AAs) receptors bind to the same receptors as natural ligands, eliciting similar (and amplified) responses. In patients with STEMI, AT1R-AAs and ETAR-AAs have been associated with a higher risk of developing microvascular obstruction and left ventricular remodeling. Both microvascular obstruction and left ventricular remodeling are associated with a poor prognosis. Purpose To assess the prognostic role of AT1R-AAs and ETAR-AAs after STEMI. Methods Consecutive STEMI patients who underwent primary percutaneous coronary intervention within 12 h after pain onset were enrolled in this prospective study. The levels of AT1R-AAs and ETAR ETAR-AAs at the time of hospital admission were measured using an enzyme-linked immunosorbent assay (ELISA) in all patients. The incidence of major adverse cardiovascular events (MACE, defined as a composite of cardiovascular mortality, myocardial re-infarction, and hospitalizations for heart failure) during follow-up was the primary outcome. Autoantibody seropositivity was defined according to ELISA’s kit manufacturer’s instructions (levels > 10 U/mL). Results Two hundred patients with STEMI were enrolled. The baseline characteristics of the patients are shown in Table 1. Of these, 110 (55%) were seronegative for both autoantibodies, 44 (22%) were seropositive for one autoantibody (but not both), and 46 (23%) were seropositive for both autoantibodies. The incidence of MACE over a 14-month median follow-up was higher in patients with double (31%) and single (25%) seropositivity than in seronegative patients (13%, p=0.009 and p=0.06, respectively). Survival free from MACE was significantly different across the different degrees of autoantibody seropositivity (Figure 1). In the multivariable Cox regression analysis, adjusted for the variables that were significant in the univariate analysis (highlighted in bold in Table 1), double seropositivity was independently associated with an increased risk of MACE (hazard ratio 2.386, 95 % CI 1.471-3.864, p<0.001). Conclusions The degree of seropositivity for AT1R-AAs and ETAR-AAs is associated with an increased risk of MACE after STEMI. Our findings provide valuable mechanistic insights into the pathophysiology of STEMI and pave the way for future therapies focused on the improvement of long-term prognosis after acute coronary syndromes.

Treatment of Systemic Sclerosis Complicated By Cardiac Arrhythmia: A Case Report

Cardiac manifestations are occasionally observed in Systemic Sclerosis patients. Primary cardiac involvement may occur as a direct consequence of the disease. Arrhythmias are also thought to be a direct result from conduction system fibrosis. Early diagnosis and treatment of arrhythmia can be rewarding for this patient as if intreated may lead to a fatal outcome. Beta blockers used to treat arrythmia may worsen Raynaud’s symptom in systemic sclerosis. So there has been a controversy regarding the treatment of arrhythmia in Systemic Sclerosis. Here we are reporting a case of Systemic Sclerosis who presented with palpitation and digital gangrene. Her resting ECG showed multiple premature ventricular complexes whereas echocardiogram did not show any significant abnormality. Then She was treated with non-selective beta blocker without any progression of her Raynaud’s. For her digital gangrene, along with other conventional treatment (like nifedipine & tadalafil) she was treated with endothelin receptor antagonist (bosentan) and showed good response. J Dhaka Med Coll. 2023; 32(1) : 92-95

High Levels of Uric Acid Upregulate Endothelin Receptors: The Role of MAPK Pathways in an in vitro Study

IntroductionUric acid (UA) is the end product of purine compounds' metabolism. There is overwhelming evidence linking hyperuricemia (high levels of UA) and cerebrovascular diseases, but the effect of high levels of UA on cerebral vessels is not fully understood. The aim of this research is to clarify how UA affect the endothelin (ET) receptor in rat cerebral arteries and the related mechanism.Material and methodsIn an in vitro setting, segments of rat cerebral arteries (n=12) were exposed to high levels of UA, either alone or in conjunction with MAPK pathway inhibitors. ET agonists were used to induce contractions that were then measured with a myograph. ET receptor expression was measured using RT-PCR (n=6), Western Blot (n=3), or immunohistochemistry (n=3) to quantify mRNA and protein levels.ResultsThe study revealed that high levels of UA notably increase ETA and ETB receptor-induced contractions and boost the expression of ET receptors in cerebral arteries when compared to that are fresh or cultured alone, suggesting that UA enhances ETA and ETB receptors. Additionally, the up-regulation of ETB receptors induced by UA was inhibited by the p38 inhibitor SB203580, the JNK inhibitor SP600125, and the ERK1/2 inhibitor U0126. SB203580 significantly blocked the increase in ETA receptor-mediated contractions induced by UA and the upregulation of ETA receptor. Neither SP600125 nor U0126 had such effect.ConclusionsHigh levels of UA stimulate the up-regulation of ET receptors in rat cerebral arteries in vitro through MAPK pathways. This study may offer novel perspectives on hyperuricemia-associated cerebrovascular diseases.

The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

Key Points Patients with IgA nephropathy and significant proteinuria are at high risk of progressive kidney function loss and kidney failure.We report the results of a clinical trial assessing the selective endothelin receptor antagonist SC0062 for the treatment of IgA nephropathy.SC0062 led to clinically meaningful improvements in proteinuria and did not increase risk of peripheral edema at higher doses. Background Endothelin receptor type A activation contributes to kidney injury in patients with IgA nephropathy. SC0062 is a novel selective endothelin receptor type A antagonist. We report the results of a phase 2 dose-finding trial to characterize the efficacy and safety of SC0062 in patients with IgA nephropathy. Methods We conducted a randomized, placebo-controlled, double-blind, clinical trial in adults with biopsy-proven IgA nephropathy and eGFR ≥30 ml/min per 1.73 m2 with urinary protein-creatinine ratio (UPCR) ≥0.75 g/g or proteinuria ≥1 g/24 hour despite using maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were randomized 1:1:1:1 to 24-week treatment with SC0062 5, 10, and 20 mg or matching placebo once daily. The primary efficacy outcome was percent change from baseline in UPCR in 24-hour urine samples after 12 weeks of treatment. Secondary end points included changes in eGFR. Safety outcomes including treatment emerging adverse events and serious adverse events were recorded. Results Overall, 131 patients (mean age 42 years [SD, 11]; mean eGFR 72 ml/min per 1.73 m2 [SD 24] and median 24-hour UPCR 1.2 g/g [25th–75th percentile, 0.9–1.5 g/g]) were randomized to placebo (n=34) or SC0062 5 mg (n=33), 10 mg (n=32), or 20 mg (n=32). All SC0062 doses reduced UPCR versus placebo throughout treatment. At week 12, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UPCR with SC0062 5, 10, and 20 mg were−27.6% (−43.0 to −8.2), −20.5% (−37.4 to 1.0), and −38.1% (−51.4 to −21.0), respectively, and at week 24 they were−22.4% (−42.2 to 4.3), −30.9% (−48.6 to −7.0), and −51.6% (−64.2 to −34.6), respectively. No differences in eGFR were observed among treatment groups. The proportion of participants with treatment emerging adverse events or serious adverse events was balanced among treatment groups. Peripheral edema was reported by 2 (6%), 1 (3%), 1 (3%) participants in the 5, 10, and 20 mg SC0062-treated groups, respectively, compared with 5 (15%) in the placebo group. Conclusions In patients with IgA nephropathy, SC0062 reduced proteinuria and did not increase risk of peripheral edema. Clinical Trial registry name and registration number: A Study to Evaluate the Efficacy and Safety of SC0062 in the Treatment of CKD, NCT05687890.

Clinical adverse events to letairis: a real-world drug safety study based on FDA Adverse Event Reporting System (FAERS)

ABSTRACT Background Letairis (ambrisentan), an endothelin receptor antagonist (ERA), is a critical medication for pulmonary arterial hypertension (PAH). Despite its efficacy, its safety profile is under scrutiny, warranting a detailed analysis. Research design and methods This study leveraged the FDA Adverse Event Reporting System (FAERS) from Q1 2007 to Q4 2023, focusing on Letairis as the primary suspect in adverse events. Employing advanced data mining techniques, such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), the study aimed to uncover safety signals. Results A total of 43,774 cases were identified, with Letairis implicated in 16,038,963 adverse event reports. There was a notable predominance of female patients (75.30%), with a median age around 64 years. Severe outcomes, including hospitalization (51.63%) and fatalities (20.44%), were prevalent. Signal strength analysis highlighted concerns in infections and infestations, as well as cardiac disorders. Conclusion The analysis underscores the need for vigilant pharmacovigilance and highlights Letairis’s potential to induce serious AEs, particularly in female and elderly populations. These findings are instrumental in guiding clinical practice and future drug safety assessments.

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

Endothelin receptor B is required for the blood pressure-lowering effect of G protein-coupled estrogen receptor 1 in ovariectomized rats.

Activation of G protein-coupled estrogen receptor 1 (GPER1) elicits antihypertensive actions in different animal models. The endothelin-1 signaling system plays a fundamental role in blood pressure regulation. Lack of functional endothelin receptor B (ETB) evokes hypertension and salt sensitivity. GPER1 and ETB interact to promote urinary sodium excretion in female rats. We hypothesized that activation of GPER1 protects against hypertension and salt sensitivity induced by ETB antagonism in female rats. Female Sprague-Dawley rats were implanted with radiotelemetry. Animals were then subjected to ovariectomy and simultaneously implanted with minipumps to deliver either the GPER1 agonist G1 or its corresponding vehicle. Two weeks post surgery, we initiated treatment of rats with the ETB antagonist A-192621. Animals were maintained on a normal-salt diet and then challenged with a high-salt diet for an additional 5 days. Assessment of mean arterial blood pressure revealed an increase in vehicle-treated, but not G1-treated, rats in response to ovariectomy. A-192621 increased blood pressure in normal-salt diet-fed vehicle- and G1-treated rats. G1 improved the circadian blood pressure rhythms that were disrupted in A-192621-treated ovariectomized rats. Thus, although systemic GPER1 activation did not protect ovariectomized rats from hypertension and salt sensitivity induced by ETB antagonism, it maintained circadian blood pressure rhythms. Functional ETB is required to elicit the antihypertensive actions of GPER1. Additional studies are needed to improve our understanding of the interaction between G protein-coupled receptors in regulating circadian blood pressure rhythm.NEW & NOTEWORTHY Systemic G protein-coupled estrogen receptor 1 (GPER1) activation in rats prevents the increase in blood pressure evoked by ovariectomy. Blockade of endothelin receptor B negates the blood pressure-lowering impact of GPER1 in ovariectomized rats. Endothelin receptor B plays an important role in mediating the blood pressure-lowering action of GPER1 activation in female rats.

Urinary Clusterin as a Pharmacodynamic Response Biomarker for the Endothelin Receptor Antagonist Atrasentan

Urinary Clusterin as a Pharmacodynamic Response Biomarker for the Endothelin Receptor Antagonist Atrasentan

Formulation Optimization and Evaluation of Patented Solid Lipid Nanoparticles of Ambrisentan for Pulmonary Arterial Hypertension.

Ambrisentan is a new endothelin receptor antagonist extensively used to manage pulmonary or pulmonary arterial hypertension. The therapeutic efficacy of Ambrisentan is limited due to its reduced solubility, higher log P (3.4), and thus less bioavailability. The recent investigation was concentrated on the improvement of solubility, and bioavailability of Ambrisentan for the therapy of hypertension via solid lipid nanoparticles (SLN) administered orally. XRD evaluated the compatibility of Ambrisentan with lipids with FTIR, DSC, and crystalline nature. The SLN was developed by High-pressure homogenization method. The Glyceryl monostearate and Tween 80 indicated the highest solubility, hence selected. The optimization was performed with Box-Behnken Design considering the concentration of GMS (X1), Tween 80 (X2), stirring speed (X3) as independent factors and particle size (Y1), entrapment efficiency (Y2) as dependent factors. The Patents on the SLN are Indian 202321053691, U.S. Patent, 10,973,798B2, U.S. Patent 10,251,960B2, U.S. Patent 2021/0069121A1 and U.S. Patent 2022/0151945A1. The optimized batch F1 showed particle size (130 nm), ZP (-18.9 mV), and entrapment efficiency (85.73 %). The dual release pattern (prompt and sustained) was achieved with the SLNloaded Ambrisentan for about 24 hours. The lyophilized sample was subjected to SEM, which also revealed a spherical shape of a colloidal dispersion with a particle size of 126 nm. Hence, the F1 batch is highly recommended for solid oral delivery and also for the pilot-plant scale-up. A marked improvement in the solubility and dissolution of Ambrisentan was attained with the SLN. Moreover, the sustained delivery via the oral route enabled the patient's comfort, compliance, and therapeutic efficacy.

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

IntroductionEndothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. MethodsEligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥1g/d, eGFR ≥30 mL/min/1.73m2, receiving a maximally-tolerated stable dose of a renin-angiotensin system inhibitor (RASi). An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24h urine protein–creatinine ratio UPCR) to Week 36 in the main stratum. Key secondary endpoints include eGFR change from baseline to Week 136, safety and tolerability. ResultsEnrolment occurred across 20 countries; 404 patients are randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 mL/min/1.73 m2 and 1.4 g/g, respectively. ConclusionThe ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RASi therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

Iron TAMs: The fallen protectors.

A new study by Folkert et al. (https://doi.org/10.1084/jem.20230420) defines an "iron-rich" subset of tumor-associated macrophages (iTAMs). The metabolism of heme leads to the degradation of the transcriptional repressor Bach1 and shapes the transcriptional profile of iTAMs. The endothelin receptor B in iTAMs signals tumor-supportive functions.

An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis.

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.

CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice

Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring Cis-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-β1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects.

Right Ventricular Hypertrophy in Spontaneously Hypertensive Rats (SHR/NHsd) Is Associated with Inter-Individual Variations of the Pulmonary Endothelin System.

Spontaneously hypertensive rats (SHRs) develop severe hypertension and subsequently left ventricular hypertrophy. Whether they also develop right ventricular hypertrophy is not clear. We analyzed 76 female SHRs (strain SHR/NHsd) and observed severe right ventricular hypertrophy in 7% of these rats (SHR-RVH). Right ventricular hypertrophy did not correlate with the age of the rats and was already seen in one rat at the pre-hypertensive state. The current study investigated the molecular fingerprint of the lung and right ventricle from SHR-RVH and compared this first to SHRs that did develop left but not right ventricular hypertrophy, and second to normotensive rats without hypertrophy. Rats with right ventricular hypertrophy had a decreased expression of the endothelin-B receptor (EDNRB) in the lung, together with an increased protein content of endothelin-1 and an increased expression of ACTA2A. Furthermore, in the right ventricle, a down-regulation of the endothelin-A receptor (EDNRA) was found, consistent with a mild phenotype. The data suggest that in a sub-group of SHR/NHsd rats, low expression of the endothelin clearance receptor (endothelin-B receptor) in the lung triggers an increase in vascular resistance to the right ventricle that then triggers hypertrophy. Our study is the first description of a genetic variant in a defined SHR strain.

Macitentan and Tadalafil Combination Therapy in Incident and Prevalent Pulmonary Arterial Hypertension: Real-World Evidence from the OPUS/OrPHeUS Studies.

Historically, patients recently (≤6months) diagnosed with pulmonary arterial hypertension (PAH; incident) have had poorer survival than those with a longer (>6months) time from PAH diagnosis (prevalent). Despite guideline recommendations for initial combination therapy for most patients with PAH, many are initiated and maintained on monotherapy. Real-world evidence to evaluate the benefit of early combination treatment in newly-diagnosed patients is lacking. Patients with PAH initiating combination therapy with the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor tadalafil (M+T) were identified from the combined dataset of the US, multicenter OPUS (prospective, observational drug registry; NCT02126943) and OrPHeUS (retrospective, medical chart review; NCT03197688) studies (2013-2020). Descriptive analyses were performed for the incident and prevalent cohorts, as well as the subcohort of incident patients who received M+T as first-line combination therapy (incident initial combination). In OPUS/OrPHeUS, 1336 patients with PAH received M+T during the observation period. For the incident [n=453 (33.9%)], incident initial combination [n=272 (20.4%)], and prevalent [n=837 (62.6%)] cohorts: median (Q1, Q3) M+T exposure was 14.2 (4.2, 27.5), 12.2 (3.2, 25.5), and 14.7 (4.5, 28.0) months. 12-month Kaplan-Meier estimates (95% confidence limits) for survival were 91.2% (87.7, 93.7), 88.5% (83.2, 92.2), and 92.9% (90.6, 94.6), for patients free from hospitalization were 59.4% (54.1, 64.4), 56.3% (49.1, 62.9), and 62.3% (58.5, 65.9), and for patients persisting on combination therapy were 68.6% (63.9, 72.8), 65.0% (58.8, 70.6) and 66.9% (63.5, 70.0). Adverse events (OPUS only) were reported in 77.8%, 80.2%, and 80.3% of patients, respectively, with no unexpected adverse events observed. Despite a historically worse prognosis, incident patients receiving M+T, including as initial combination therapy, had similar survival and hospitalization as prevalent patients. Safety profiles were similar across cohorts. Together, these data support the use of early combination therapy with macitentan and tadalafil.

Early Addition of Selexipag to Double Therapy for Pulmonary Arterial Hypertension

A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied. To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i. This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023. TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT. Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up. A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90). This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

The Gq/11 family of Gα subunits is necessary and sufficient for lower jaw development.

Vertebrate jaw development is coordinated by highly conserved ligand-receptor systems such as the peptide ligand Endothelin 1 (Edn1) and Endothelin receptor type A (Ednra), which are required for patterning of lower jaw structures. The Edn1/Ednra signaling pathway establishes the identity of lower jaw progenitor cells by regulating expression of numerous patterning genes, but the intracellular signaling mechanisms linking receptor activation to gene regulation remain poorly understood. As a first step towards elucidating this mechanism, we examined the function of the Gq/11 family of Gα subunits in zebrafish using pharmacological inhibition and genetic ablation of Gq/11 activity and transgenic induction of a constitutively active Gq protein in edn1 -/- embryos. Genetic loss of Gq/11 activity fully recapitulated the edn1 -/- phenotype, with genes encoding G11 being most essential. Furthermore, inducing Gq activity in edn1 -/- embryos not only restored Edn1/Ednra-dependent jaw structures and gene expression signatures but also caused homeosis of the upper jaw structure into a lower jaw-like structure. These results indicate that Gq/11 is necessary and sufficient to mediate the lower jaw patterning mechanism for Ednra in zebrafish.