Calcium channel blockers in patients with pulmonary arterial hypertension receiving PAH-specific treatment.

BACKGROUND: Calcium channel blockers (CCB) are the first effective therapy for vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH). However, the advent of modern PAH-specific drugs may undermine the role of vasoreactivity tests and CCB treatment. We aimed to clarify the effect of acute vasoreactivity testing and CCB on patients with IPAH receiving PAH-specific treatment. METHODS: We retrospectively investigated consecutive patients with IPAH (n = 136) diagnosed between 2000 and 2020 and collected data from patients who underwent acute vasoreactivity testing using inhaled nitric oxide (NO). The effects of vasoreactivity testing and CCB therapy were reviewed. Long-term survival was analysed using the Kaplan-Meier method. RESULTS: Acute vasoreactivity testing was performed in 49% of patients with IPAH (n = 67), including 23 patients (34%) receiving PAH-specific therapy without vasoreactivity testing. Eight patients (12%), including three patients (4.4%) receiving PAH-specific therapy, presented acute responses at vasoreactivity testing. They received high-dose CCB therapy (CCB monotherapy for five patients [7.5%] and CCB therapy and PAH-specific therapy for three patients [4.4%]). They presented a significant improvement in clinical parameters and near-normalisation of haemodynamics (mean pulmonary arterial pressure decreased from 46 [interquartile range: 40-49] to 19.5 [interquartile range: 18-23] mmHg [P < .001] at 1-year follow-up). All eight vasoreactive responders receiving CCB therapy showed better long-term survival than non-responders treated with PAH-specific therapy (P < .001). CONCLUSIONS: CCB therapy benefited patients with IPAH who showed acute response to vasoreactivity testing using inhaled NO, even when receiving modern PAH-specific therapy. Acute vasoreactive responders may benefit more from CCB than from PAH-specific therapy.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

Purpose: The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Methods: Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. Results: We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Conclusion: Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

Jiedu Quyu Decoction mitigates monocrotaline-induced right-sided heart failure associated with pulmonary artery hypertension by inhibiting NLRP3 inflammasome in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Right-side heart failure could accelerate mortality in patients of pulmonary hypertension, Jiedu Quyu Decoction (JDQYF) was used to manage pulmonary hypertension, but its right-sided heart protective effect associated with pulmonary artery hypertension is still unclear. AIM OF THE STUDY: Here, we evaluated the therapeutic effect of JDQYF on monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension in Sprague-Dawley (SD) rats and investigated the potential mechanism of action. MATERIALS AND METHODS: The main chemical components of JDQYF were detected and analyzed using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. The effects of JDQYF were investigated using a rat model of monocrotaline-induced right-sided heart failure associated with pulmonary arterial hypertension. We assessed the morphology of cardiac tissue using histopathology and the structure and function of the right heart using echocardiography. The biomarkers of heart failure, atrial natriuretic peptide and B-type natriuretic peptide, as well as serum pro-inflammatory markers, interleukin (IL)-1ß, and IL-18, were measured by enzyme-linked immunosorbent assay (ELISA). Furthermore, the mRNA and protein expression levels of NLRP3 (NOD-, LRR-, and pyrin domain-containing 3), capase-1, IL-1ß, and IL-18 in the right heart tissue were examined by real-time quantitative reverse transcription PCR and western blotting. RESULTS: JDQYF improved ventricular function, alleviated pathological lesions in the right cardiac tissue, reduced the expression levels of biomarkers of heart failure and serum pro-inflammatory factors (IL-1ß and IL-18), and downregulated the mRNA and protein expression levels of NLRP3, caspase-1, IL-1ß, and IL-18 in the right cardiac tissue. CONCLUSIONS: JDQYF possesses cardioprotective effect against right heart failure induced by pulmonary arterial hypertension, possibly owing to reduction of cardiac inflammation through the inhibition of NLRP3 inflammasome activation.

Sickle Cell Disease (SCD) Leading to Pulmonary Arterial Hypertension (PAH) and Cholelithiasis (CL).

Sickle cell disease (SCD) consists of a variety of hereditary hemoglobinopathies linked to alterations in the beta component of the hemoglobin (Hb) molecule. Acute SCD manifestations include stroke, acute chest syndrome (ACS), and pain, whereas chronic manifestations include avascular necrosis, chronic renal disease, and gallstones. This case report describes a rare instance of SCD-related pulmonary arterial hypertension (PAH) and cholelithiasis (CL). Following investigations, such as high-resolution CT scan thorax, chest X-ray, two-dimensional echocardiography, and ultrasonography of the abdomen and pelvis, PAH and CL were confirmed. The medical intervention mainly involved oxygenation, IV fluids, IV antibiotics, simple packed red blood cell transfusion (SBCT), folic acid, calcium supplementation, hydroxyurea, chest physiotherapy, and respiratory muscle strengthening exercises. The surgical intervention for CL was planned. Hence, the learning point from this case is that early multidisciplinary approach should be taken in order to control the progression of SCD.

Rapid separation and binding configuration prediction of the components in Danshen decoction to endothelin A receptor using affinity chromatography and molecular dynamics simulation.

As a famous traditional Chinese formula, Danshen Decoction has the potential to relieve the pain of pulmonary arterial hypertension patients, however, the functional components remain unknown. Herein, we reported a method to screen the functional components in Danshen Decoction targeting endothelin receptor A, an accepted target for the treatment of the disease. The receptor was functionalized on the macroporous silica gel through an epidermal growth factor receptor fusion tag and its covalent inhibitor. Using the affinity gel as the stationary phase, the bioactive compound was identified as salvianolic acid B by mass spectrometry. The binding kinetic parameter (dissociation rate constants kd ) of salvianolic acid B with the receptor was determined via peak profiling. Using the specific ligands of the receptor as probes, the binding configuration prediction of salvianolic acid B with the receptor was performed by molecular dynamics simulation. Our results indicated that salvianolic acid B is a potential bioactive compound in Danshen Decoction targeting the receptor. This work showed that receptor chromatography in combination with molecular dynamics simulation is applicable to predicting the binding kinetics and configuration of a ligand to a receptor, providing crucial insight for the rational design of drugs that recognize functional proteins.

Differential effect of basal vitamin D status in monocrotaline induced pulmonary arterial hypertension in normal and vitamin D deficient rats: Possible involvement of eNOS/TGF-ß/α-SMA signaling pathways.

Vitamin D deficiency is common and linked to poor prognosis in pulmonary arterial hypertension (PAH). We investigated the differential effect of basal vitamin D levels in monocrotaline (MCT) induced PAH in normal and vitamin D deficient (VDD) rats. Rats were fed a VDD diet and exposed to filtered fluorescent light to deplete vitamin D. Normal rats were pretreated with vitamin D 100 IU/d and treated with vitamin D 100 and 200 IU/d, while VDD rats received vitamin D 100 IU/d. Vitamin D receptor (VDR) silencing was done in human umbilical vein endothelial cells (HUVECs) using VDR siRNA. Calcitriol (50 nM/mL) was added to human pulmonary artery smooth muscle cells (HPASMCs) and HUVECs before and after the exposure to TGF-ß (10 ng/mL). Vitamin D 100 IU/d pretreatment in normal rats up-regulated the expression of eNOS and inhibited endothelial to mesenchymal transition significantly and maximally. Vitamin D 100 IU/d treatment in VDD rats was comparable to vitamin D 200 IU/d treated normal rats. These effects were significantly attenuated by L-NAME (20 mg/kg), a potent eNOS inhibitor. Exposure to TGF- ß significantly reduced the expression of eNOS and increased the mesenchymal marker expression in normal and VDR-silenced HUVECs and HPASMCs, which were averted by treatment and maximally inhibited by pretreatment with calcitriol (50 nM). To conclude, this study provided novel evidence suggesting the beneficial role of higher basal vitamin D levels, which are inversely linked with PAH severity.

Case Report: Vitamin C combined with multiple micronutrient deficiencies is associated with pulmonary arterial hypertension in children with autistic spectrum disorder.

Children with developmental and behavioral problems including autistic spectrum disorders (ASDs) may have inappropriate feeding behaviors, which leads to an increased risk of multiple nutrient deficiencies. Vitamin C deficiency is one of the common nutrient deficiencies reported in children with inappropriate feeding. This case report illustrates two cases of ASD children with a clinical presentation of pulmonary arterial hypertension, a rare presentation of vitamin C deficiency. Vitamin C supplementation, pulmonary vasodilator, and supportive treatment were provided. Patients could recover from the illness and could be discharged from the hospital in a short time. In addition to vitamin C, the patients also had multiple micronutrient deficiencies. Nutrition counseling was given and micronutrient supplement was continued until follow-up. Regular nutrition assessment and counseling among children with ASD are needed to prevent nutrient deficiencies which may lead to life-threatening complications.

Pulmonary arterial hypertension sensitive to calcium channel blocker, but not advanced pulmonary hypertension treatment: a case report.

Background: Calcium channel blockers (CCB), the first accepted treatment, is effective only in a small number of idiopathic pulmonary arterial hypertension (I-PAH) patients with vasoreactivity [these patients are identified by a positive acute pulmonary vasoreactive test (AVT) response]. While the majority of I-PAH patients is non-vasoreactive and CCB non-responders, modern advanced pulmonary hypertension (PH)-specific therapies, which act on one of the three different mechanistic pathways-endothelin, nitric oxide (NO), and prostacyclin pathways, are effective. Treatment response to advanced PH-specific vasodilators in PAH patients with vasoreactivity is unknown. Case summary: A 30-year-old woman with I-PAH was referred to our centre with worsening symptoms and deteriorating PH. She was being administered oral triple combination of advanced PH-specific treatment including a phosphodiesterase-5 inhibitor, an endothelin receptor antagonist, and a long-acting prostacyclin analogue. The patient showed positive AVT with NO inhalation while on these advanced PH-specific drugs. We added high-dose CCB, which dramatically normalized her pulmonary blood pressure without further symptoms, and she has remained stable for 5 years. Discussion: Our case describes a PAH patient with vasoreactivity, who was resistant to three different types of advanced PH-specific vasodilators but was exclusively sensitive to CCB treatment. Some CCB responders may have a specific CCB-sensitive PAH phenotype refractory to other pulmonary vasodilators. This case highlights the role of identifying CCB responders in this era of use of modern, advanced PH-specific vasodilators. The investigation of the mechanisms underlying CCB sensitivity in PAH is necessary.

Role of solid lipid nanoparticle for the delivery of Lipophilic Drugs and Herbal Medicines in the treatment of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is an uncommon condition marked by elevated pulmonary artery pressure that leads to right ventricular failure. The majority of drugs are now been approved by FDA for PAH, however, several biopharmaceutical hindrances lead to failure of the therapy. Various novel drug delivery systems are available in the literature from which lipid-based nanoparticles i.e. solid lipid nanoparticle is widely investigated for improving the solubility and bioavailability of drugs. In this paper, the prototype phytoconstituents used in pulmonary arterial hypertension have limited solubility and bioavailability. We highlighted the novel concepts of SLN for lipophilic phytoconstituents with their potential applications. This paper also reviews the present state of the art regarding production techniques for SLN like High-Pressure Homogenization, Micro-emulsion Technique, and Phase Inversion Temperature Method, etc. Furthermore, toxicity aspects and in vivo fate of SLN are also highlighted in this review. In a nutshell, safer delivery of phytoconstituents by SLN added a novel feather to the cap of successful drug delivery technologies.

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling.

BACKGROUND: Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. METHODS: Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. RESULTS: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. CONCLUSION: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Safety of chronic high-dose calcium channel blockers exposure in children with pulmonary arterial hypertension.

Background: Chronic calcium channel blockers (CCBs) are indicated in children with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population. Methods: Patients aged 3 months to 18 years who were diagnosed with IPAH/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed. Results: Thirty-two eligible children were enrolled in the study, with a median age of 9 (6-11) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8-16.8) mg/kg/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5-28.5) mg/kg/day vs. 12.7 (6.6-14.4) mg/kg/day, P < 0.05. Patients were followed up for a median period of 6.2 (2.6-10.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported. Conclusion: Diltiazem was used in a very high dose for eligible children with IPAH/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.

Effects of Fdft 1 gene silencing and VD3 intervention on lung injury in hypoxia-stressed rats.

BACKGROUND: Hypoxia can induce lung injury such as pulmonary arterial hypertension and pulmonary edema. And in the rat model of hypoxia-induced lung injury, the expression of Farnesyl diphosphate farnesyl transferase 1 (Fdft 1) was highly expressed and the steroid biosynthesis pathway was activated. However, the role of Fdft 1 and steroid biosynthesis pathway in hypoxia-induced lung injury remains unclear. OBJECTIVE: The study aimed to further investigate the relationship between Fdft1 and steroid biosynthesis pathway with hypoxia-induced lung injury. METHODS: A rat model of lung injury was constructed by hypobaric chamber with hypoxic stress, the adenovirus interference vector was used to silence the expression of Fdft 1, and the exogenous steroid biosynthesis metabolite Vitamin D3 (VD3) was used to treat acute hypoxia-induced lung injury in rats. RESULTS: Sh-Fdft 1 and exogenous VD3 significantly inhibited the expression of Fdft 1 and the activation of the steroid pathway in hypoxia-induced lung injury rats, which showed a synergistic effect on the steroid activation pathway. In addition, sh-Fdft 1 promoted the increase of pulmonary artery pressure and lung water content, the decrease of oxygen partial pressure and oxygen saturation, and leaded to the increase of lung cell apoptosis and the aggravation of mitochondrial damage in hypoxia-stressed rats. And VD3 could significantly improve the lung injury induced by hypoxia and sh-Fdft 1 in rats. CONCLUSIONS: Fdft 1 gene silencing can promote hypoxic-induced lung injury, and exogenous supplement of VD3 has an antagonistic effect on lung injury induced by Fdft 1 gene silencing and hypoxic in rats, suggesting that VD3 has a preventive and protective effect on the occurrence and development of hypoxia-induced lung injury.

Potential of the TRPM7 channel as a novel therapeutic target for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an intractable vascular disease characterized by a progressive increase in pulmonary vascular resistance caused by pulmonary vascular remodeling, which ultimately leads to right-sided heart failure. PAH remains incurable, despite the development of PAH-targeted therapeutics centered on pulmonary artery relaxants. It is necessary to identify the target molecules that contribute to pulmonary artery remodeling. Transient receptor potential (TRP) channels have been suggested to modulate pulmonary artery remodeling. Our study focused on the transient receptor potential ion channel subfamily M, member 7, or the TRPM7 channel, which modulates endothelial-to-mesenchymal transition and smooth muscle proliferation in the pulmonary artery. In this review, we summarize the role and expression profile of TRPM7 channels in PAH progression and discuss TRPM7 channels as possible therapeutic targets. In addition, we discuss the therapeutic effect of a Chinese herbal medicine, Ophiocordyceps sinensis (OCS), on PAH progression, which partly involves TRPM7 inhibition.

l-Carnitine therapy improves right heart dysfunction through Cpt1-dependent fatty acid oxidation.

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy that ultimately leads to elevated pulmonary pressure and death by right ventricular (RV) failure, which occurs in part due to decreased fatty acid oxidation and cytotoxic lipid accumulation. In this study, we tested the hypothesis that decreased fatty acid oxidation and increased lipid accumulation in the failing RV is driven, in part, by a relative carnitine deficiency. We then tested whether supplementation of l-carnitine can reverse lipotoxic RV failure through augmentation of fatty acid oxidation. In vivo in transgenic mice harboring a human BMPR2 mutation, l-carnitine supplementation reversed RV failure by increasing RV cardiac output, improving RV ejection fraction, and decreasing RV lipid accumulation through increased PPARγ expression and augmented fatty acid oxidation of long chain fatty acids. These findings were confirmed in a second model of pulmonary artery banding-induced RV dysfunction. In vitro, l-carnitine supplementation selectively increased fatty acid oxidation in mitochondria and decreased lipid accumulation through a Cpt1-dependent pathway. l-Carnitine supplementation improves right ventricular contractility in the stressed RV through augmentation of fatty acid oxidation and decreases lipid accumulation. Correction of carnitine deficiency through l-carnitine supplementation in PAH may reverse RV failure.

Srolo Bzhtang reduces inflammation and vascular remodeling via suppression of the MAPK/NF-κB signaling pathway in rats with pulmonary arterial hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE: Srolo Bzhtang (SBT), which consists of Solms-laubachia eurycarpa, Bergenia purpurascens, Glycyrrhiza uralensis, and lac secreted by Laccifer lacca Kerr (Lacciferidae Cockerell), is a well-known traditional Tibetan medicinal formula and was documented to cure "lung-heat" syndrome by eliminating "chiba" in the ancient Tibetan medical work Four Medical Tantras (Rgyud bzhi). Clinically, it is a therapy for pulmonary inflammatory disorders, such as pneumonia, chronic bronchitis, and chronic obstructive pulmonary disease. However, whether and how SBT participates in pulmonary arterial hypertension (PAH) is still unclear. AIM OF THE STUDY: We aimed to determine the role of SBT in attenuating pulmonary arterial pressure and vascular remodeling caused by monocrotaline (MCT) and hypoxia. To elucidate the potential mechanism underlying SBT-mediated PAH, we investigated the changes in inflammatory cytokines and mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. MATERIALS AND METHODS: MCT- and hypoxia-induced PAH rat models were used. After administering SBT for four weeks, the rats were tested for hemodynamic indicators, hematological changes, pulmonary arterial morphological changes, and the levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in serum and lung tissues. Protein expression of the MAPK/NF-κB signaling pathway was determined using western blotting. RESULTS: SBT reduced pulmonary arterial pressure, vascular remodeling, and the levels of inflammatory cytokines induced by MCT and hypoxia in rats. Furthermore, SBT significantly suppressed the MAPK/NF-κB signaling pathway. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that SBT alleviates MCT- and hypoxia-induced PAH in rats, which is related to its anti-inflammatory actions involving inhibition of the MAPK/NF-κB signaling pathway.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat.

Introduction: Current targeted pulmonary arterial hypertension (PAH) therapies have improved lung hemodynamics, cardiac function, and quality of life; however, none of these have reversed the ongoing remodeling of blood vessels. Considering notopterol, a linear furocoumarin extracted from the root of traditional Chinese medicine Qiang-Huo (Notopterygium incisum), had shown the antiproliferative and anti-inflammatory properties in previous studies, we hypothesized that it could play a role in ameliorating PAH. Methods: In vivo, we conducted monocrotaline (MCT) induced PAH rats and treated them with notopterol for 3 weeks. Then, the rats were examined by echocardiography and RV catheterization. The heart and lung specimens were harvested for the detection of gross examination, histological examination and expression of inflammatory molecules. In vitro, human pulmonary arterial smooth muscle cells (HPASMCs) were treated with notopterol after hypoxia; then, cell proliferation was assessed by cell counting kit-8 and Edu assay, and cell migration was detected by wound healing assays. Results: We found that notopterol improved mortality rate and RV function while reducing right ventricular systolic pressure in MCT-induced PAH rats. Furthermore, notopterol reduced right ventricular hypertrophy and fibrosis, and it also eased pulmonary vascular remodeling and MCT-induced muscularization. In addition, notopterol attenuated the pro-inflammatory factor (IL-1ß, IL-6) and PCNA in the lungs of PAH rats. For the cultured HPASMCs subjected to hypoxia, we found that notopterol can inhibit the proliferation and migration of HPASMCs. Conclusion: Our studies show that notopterol exerts anti-inflammatory and anti-proliferative effects in the pulmonary arteries, which may contribute to prevention of PAH.

Iron deficiency and pulmonary arterial hypertension.

The purpose of this review article is to provide a comprehensive review of iron deficiency in the setting of pulmonary arterial hypertension (PAH) and to evaluate the utility of iron supplementation in PAH. Iron deficiency is present in 33%-46% of patients with PAH and has been associated with reduced exercise capacity, compromised oxygen handling, deterioration of right ventricular function, and even mortality. Iron homeostasis and the pathophysiology of PAH are highly intertwined, which has inspired the use of iron supplementation in patients with iron deficiency and PAH. A literature search was performed to identify all available evidence on iron supplementation for PAH. Limited evidence has suggested poor oral bioavailability of oral iron dosed three times a day, but newer formulations such as ferrous maltol may provide better absorption and clinical benefit, especially when dosed less frequently, such as every other day. Intravenous (IV) iron has been shown in observational studies to improve outcomes, but the single randomized control trial in patients without anemia has failed to show benefits in any measure of exercise tolerance. Larger randomized control studies on oral iron with good bioavailability or IV iron in patients with anemia are warranted to explore the potential utility of iron supplementation in patients with PAH.

Potential mechanisms of Qili Qiangxin capsule to prevent pulmonary arterial hypertension based on network pharmacology analysis in a rat model.

Background: Qili Qiangxin capsule (QQC), a traditional Chinese medicine, has recently been approved to treat pulmonary arterial hypertension (PAH). However, the multi-target mechanism through which QQC acts on PAH has not been clarified. The objective of this study was to explore the pharmacological processes of QQC for treating PAH. Methods: The rat model of PAH was established by administering monocrotaline (MCT). The impact of QQC on PAH was studied in treatment group that received QQC orally over a period of 4 weeks. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was searched for active compounds and QQC targets that were then identified and downloaded. Then, PAH-related targets were obtained from five databases [GeneCards, DrugBank, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and PharmGKB]. The QQC targets for PAH were compiled after they had been overlapped with one another. Furthermore, the STRING network platform, the Cytoscape tool, networks of protein-protein interaction (PPI) were used, and core target analyses were carried out. Moreover, molecular docking techniques were employed in this research. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies of overlapping targets were carried out using the R software (version: 4.0.5; Lucent Technologies Co., Ltd., China). Finally, we verified the synergistic action mechanisms using western blotting and immunofluorescence analysis on PAH rats who were treated with or without QQC. Results: The search of the TCMSP database showed that there were 11 active ingredients in QQC that treated PAH. PPI network showed that AKT1, TP53, JUN, and MAPK1 were the most important targets in the treatment of PAH. Moreover, Molecular docking techniques showed that the affinity between the bioactive compounds in QQC and their PAH targets was strong. In vivo experiments demonstrated that QQC may attenuate the progression of MCT-stimulated PAH in rats. Furthermore, the protective effect was mediated by inhibiting the PI3K/AKT pathway. The active compounds mainly included quercetin, kaempferol, formononetin, and luteolin, which had good docking scores and targeted the AKT protein. Conclusions: QQC might activate the PI3K/AKT signaling pathway to ameliorate MCT-induced PAH. These findings support the clinical use of QQC and provide the foundation for further studies.

Polygonum tinctorium leaves suppress sodium dextran sulfate-induced colitis through interleukin-10-related pathway.

Indigo naturalis, a herbal medicine purified from indigo-containing plants, such as Strobilanthes cusia, Isatis tinctoria, and Polygonum tinctorium, has been reported to be useful in the treatment of ulcerative colitis by activating the aryl hydrocarbon receptor. However, the aryl hydrocarbon receptor pathway causes crucial side effects, such as pulmonary arterial hypertension. Although P. tinctorium is one of the plant derivatives of indigo naturalis, it is not identical to it. To date, the pure leaves of P. tinctorium have not been reported to ameliorate ulcerative colitis. Therefore, we investigated the effect of pure P. tinctorium leaves, which are consumed in some regions, on experimental colitis induced in mice using sodium dextran sulfate. We found that P. tinctorium leaves ameliorated weight loss (P < 0.01) and pathological inflammatory changes in the colon (P < 0.05), enhanced mRNA expression of interleukin-10 (P < 0.05), and decreased expression of tumor necrosis factor-in colonic tissues (P < 0.05), as determined using quantitative real-time reverse transcription polymerase chain reaction. The intraperitoneal administration of an aryl hydrocarbon receptor antagonist did not antagonize the inhibition of mucosal destruction, whereas an anti-interleukin-10 receptor antibody did. These results suggest that P. tinctorium ameliorate sodium dextran sulfate-induced intestinal inflammation via interleukin-10-related pathway, independent of the aryl hydrocarbon receptor pathway. P. tinctorium leaves have the potential to be a new, safe treatment for ulcerative colitis.