Arterial Hypertension In Rats Research Articles

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Cordycepin against Pulmonary Arterial Hypertension in Rats.

Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline (MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used, respectively. Through Network Pharmacology and molecular docking, the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.

Functional Changes in the Expression of the Aqp4 Gene in the Hypothalamus Under the Influence of Drinking Regimen and Arterial Hypertension in Rats

Aquaporin-4 (AQP4) is the main water channel in the central nervous system. AQP4 is densely expressed in brain structures suggesting a crucial role in water transport in normal conditions and in disease. The effect of changes in drinking regime (water-deprivation and hyperhydration) and inherited arterial hypertension on the expression of the AQP4 water channel gene in the hypothalamus, the center of regulation of visceral functions, was studied. It was shown that the level of the Aqp4 mRNA in hyperhydrated animals more than 1.5 times lower than in animals with water-deprivation. This decrease in the Aqp4 gene expression in the hypothalamus may be associated with the ability to prevent cytotoxic edema during increased fluid intake. Rats with inherited stress induced arterial hypertension (ISIAH) are characterized by an increased level of Aqp4 mRNA in the hypothalamus, which suggests the involvement of this channel in processes associated with the regulation of brain water balance during arterial hypertension and the prevention of vasogenic cerebral edema. Thus, the presence of the AQP4 water channel in the brain, associated with the protection of brain cells, is functionally determined by the state of the body. This may be evidenced by bidirectional changes in the Aqp4 gene expression during hyperhydration and arterial hypertension.

The Impact of Highly Selective Thoracic Sympathectomy on the Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by persistently elevated pulmonary artery pressure and vascular resistance. Sympathetic overactivity in hypertension participates in pulmonary vascular remodeling and heart failure. The present study aims to explore the efficacy of highly selective thoracic sympathectomy (HSTS) on lowering pulmonary artery pressure, reversing pulmonary vascular remodeling, and improving right ventricular function in rats. A total of 24 Sprague-Dawley rats were randomly assigned into the control group (n = 8) and experimental group (n = 16). Rats in the control group were intraperitoneally injected with 0.9% normal saline, and those in the experimental group were similarly administered with received monocrotaline (MCT) injections at 60 mg/kg. Two weeks later, rats in the experimental group were further subdivided randomly into the MCT-HSTS group (n = 8) and MCT-sham group (n = 8), and they were surgically treated with HSTS and sham operation, respectively. Two weeks later, significantly lowered mean pulmonary artery pressure (mPAP), pulmonary artery systolic pressure (sPAP), and the ratio of sPAP to femoral artery systolic pressure (sFAP) were detected in the MCT-HSTS group than those of the MCT-sham group. In addition, rats in the MCT-HSTS group presented a significantly lower ratio of vascular wall area to the total vascular area (WT%), right ventricular hypertrophy index, and degrees of right ventricular fibrosis and lung fibrosis in comparison to those of the MCT-sham group. HSTS significantly downregulated protein levels of inflammasomes in pulmonary artery smooth muscle cells (PASMCs). Collectively, HSTS effectively reduces pulmonary artery pressure, pulmonary arteriolar media hypertrophy, and right ventricular hypertrophy in MCT-induced PAH rats. It also exerts an anti-inflammatory effect on PASMCs in PAH rats by suppressing inflammasomes and the subsequent release of inflammatory cytokines.

Mechanisms of cordycepin in the treatment of pulmonary arterial hypertension in rats based on metabonomics and transcriptomics

Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53–P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 μM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

Transcriptome-Wide N6-Methyladenosine Alternations in Pulmonary Arteries of Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats and Novel Therapeutic Targets.

N6-methyladenosine (m6A) is a post-transcriptional epigenetic change with transcriptional stability and functionality regulated by specific m6A-modifying enzymes. However, the significance of genes modified by m6A and enzymes specific to m6A regulation in the context of pulmonary arterial hypertension (PAH) remains largely unexplored. MeRIP-seq and RNA-seq were applied to explore variances in m6A and RNA expression within the pulmonary artery tissues of control and monocrotaline-induced PAH rats. Functional enrichments were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. To screen candidate m6A-related genes, the STRING and Metascape databases were used to construct a protein-protein interaction network followed by a real-time PCR validation of their expression. The expression level of an m6A regulator was further investigated using immunohistochemical staining, immunofluorescence, and Western blot techniques. Additionally, proliferation assays were conducted on primary rat pulmonary artery smooth muscle cells (PASMCs). We identified forty-two differentially expressed genes that exhibited either hypermethylated or hypomethylated m6A. These genes are predominantly related to the extracellular matrix structure, MAPK, and PI3K/AKT pathways. A candidate gene, centromere protein F (CENPF), was detected with increased expression in the PAH group. Additionally, we first identified an m6A reader, leucine rich pentatricopeptide repeat containing (LRPPRC), which was downregulated in the PAH rat model. The in vitro downregulation of Lrpprc mediated by siRNA resulted in the enhanced proliferation and elevated expression of Cenpf mRNA in primary rat PASMCs. Our study revealed a modified transcriptome-wide m6A landscape and associated regulatory mechanisms in the pulmonary arteries of PAH rats, potentially offering a novel target for therapeutic strategies in the future.

Zang Siwei Qingfei Mixture Alleviates Pulmonary Arterial Hypertension in Rats: Integrated Network Pharmacology and Metabolomics

Purpose: Pulmonary arterial hypertension (PAH) is a fatal condition characterized by poor control of pulmonary hemodynamics and vascular development. Zang Siwei Qingfei mixture (ZSQM) is a traditional Chinese medicine formula used for the treatment of chronic respiratory diseases. However, the underlying mechanism of ZSQM for treating PAH remains unclear.Methods: A PAH rat model was established after monocrotaline (MCT) injection, and pulmonary hemodynamic features and pathological changes were evaluated. The candidate targets of ZSQM against PAH were discovered using network pharmacology. Then, molecular docking was used to validate the discovered key targets. Moreover, serum metabolomics was used to identify differential metabolites. The metabolomics and network pharmacology integrated network was constructed.Results: ZSQM alleviated MCT‐induced pulmonary vascular injury and vascular remodeling. We found ZSQM core component chrysin and six hub genes according to network pharmacology, including CYP2C19, CASP8, PTK2, VEGFA, FLT4, and TNNI3. Molecular docking revealed strong binding affinities between key targets and chrysin. Meanwhile, western blotting results validated significant changes in the expression of these key targets. Subsequently, we confirmed that chrysin existed in the ZSQM by HPLC–MS. In addition, a total of 19 metabolites with potential significance were identified to be implicated in the therapeutic mechanisms of ZSQM. The further integrated analysis indicated an interconnection between these key targets, their related core metabolites (12(S)HETE, ascorbate, succinate, vitamin C, and L‐arginine), and metabolic pathways.Conclusion: The study, employing metabolomics and network pharmacology, has concluded that ZSQM has the potential to enhance the treatment of PAH by targeting multiple pathways and molecular targets. This finding suggests that ZSQM could serve as a promising alternative therapy for PAH.

Retraction Note: Effect of atorvastatin on pulmonary arterial hypertension in rats through PI3K/AKT signaling pathway.

The article "Effect of atorvastatin on pulmonary arterial hypertension in rats through PI3K/AKT signaling pathway", by Y.-Y. Wang, X.-D. Cheng, H. Jiang, published in Eur Rev Med Pharmacol Sci 2019; 23 (23): 10549-10556-DOI: 10.26355/eurrev_201912_19696-PMID: 31841211 has been retracted by the Authors. After publication, issues were raised on PubPeer about the reliability of the published results, in particular, of Figures 2 and 3. The authors stated that the article presents some inaccuracies as the data cannot be repeated by further research. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19696.

Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22-alpha (SM22-α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF-β), and connective tissue growth factor (CTGF) in a dose-dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α-smooth muscle actin (α-SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin-related transcription factor-A (MRTF-A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF-A/myocardin) transcription complex to treat PAH.

Effect of Vitamin D in Experimental Pulmonary Arterial Hypertension in Rats: Possible Role of eNOS-mediated Signalling Pathways.

Effect of Vitamin D in Experimental Pulmonary Arterial Hypertension in Rats: Possible Role of eNOS-mediated Signalling Pathways.

STING mediates SU5416/hypoxia-induced pulmonary arterial hypertension in rats by regulating macrophage NLRP3 inflammasome activation

BackgroundThe NLRP3 inflammasome in macrophages is known to promote infection-related vascular growth, and NLRP3 inflammasome activation interacts with PAH. STING is a crucial inflammatory reaction link that can increase the overexpression of NLRP3. However, the expression and effect of STING in PAH have not been elucidated. We examined the expression and articulation of STING in PAH and researched its hidden mechanism. MethodsA SU5416 plus hypoxia (Su/Hy)-induced rat model of PAH was constructed to examine STING activation. Su/Hy induced PAH rats were given a prophylactic injection of STING the inhibitor C-176. After modeling, hemodynamic changes, right ventricular hypertrophy index, lung morphological features, inflammasome activation, and proinflammatory cytokine secretion levels were assessed. In addition, the STING agonist DMXAA or inhibitor C-176 was used to interfere with LPS-induced BMDMs, NLRP3 inflammasome activation and cytokine secretion were examined, and the effect on PASMCs was evaluated in a coculture system. ResultsSTING expression increased significantly in the lung tissue of Su/Hy-treated PAH rats compared with normoxia-treated rats. Moreover, STING inhibitors can alleviate the Su/Hy-induced increase in pulmonary artery pressure and restrain the activation of the NLRP3 inflammasome and proinflammatory cytokines. In vitro experiments confirmed that STING affected the expression of the NLRP3 inflammasome and the secretion of inflammatory cytokines in BMDMs and promoted the proliferation of PASMCs in the coculture system. ConclusionOur study shows that STING is activated in Su/Hy-induced PAH and boosts the actuation of the macrophage NLRP3 inflammasome to advance the inflammatory response and vascular proliferation in rats with Su/Hy-induced pulmonary hypertension.

Curcumol suppresses endothelial-to-mesenchymal transition via inhibiting the AKT/GSK3β signaling pathway and alleviates pulmonary arterial hypertension in rats

Endothelial dysfunction is essential in pulmonary arterial hypertension (PAH) pathogenesis and is considered to be a therapeutic target of PAH. Curcumol is a bioactive sesquiterpenoid with pharmacological properties including restoring endothelial cells damage. This study aimed to evaluate the effect of curcumol on PAH rats and investigate its possible mechanisms. PAH was induced by subcutaneous injection of 60 mg/kg monocrotaline (MCT) in male Sprague Dawley rats. Curcumol (12.5, 25, and 50 mg/kg/day) were administered by intragastric administration for 3 weeks. The results demonstrated that curcumol dose-dependently alleviated MCT-induced right ventricular hypertrophy and pulmonary arterial wall thickness. In addition, endothelial-to-mesenchymal transition (EndMT) in the pulmonary arteries of MCT-challenged rats was inhibited after curcumol treatment, as evidenced by the restored expressions of endothelial and myofibroblast markers. The possible pharmacological mechanisms of curcumol were analyzed using network pharmacology. After screening the common therapeutic targets of PAH and curcumol by searching related databases and comparison, pathway enrichment was performed and AKT/GSK3β was screened out as a possible signaling pathway which was relevant to the therapeutic mechanism of curcumol on PAH. Western blot analysis verified this in lung tissues. Moreover, combination of TNF-α, TGF-β1 and IL-1β-induced EndMT in primary rat pulmonary arterial endothelial cells were blocked by curcumol, and this effect was resembled by PI3K/AKT inhibitor LY294002. Above all, our study suggested that curcumol inhibited EndMT via inhibiting the AKT/GSK3β signaling pathway, which may contribute to its alleviated effect on PAH. Curcumol may be developed as a therapeutic for PAH in the future.

Beneficial effects of berberine against pulmonary complications of experimental pulmonary arterial hypertension in rats and some relevant mechanisms.

Pulmonary arterial hypertension (PAH) is a severe disease that leads to pulmonary vascular remodeling characterized by a rise in pulmonary vascular resistance and pressure. We assessed the effects of an herbal compound, berberine (BB), and some related mechanisms on PAH in rats. Male Wistar rats were assigned to seven groups: control, monocrotaline (MCT), MCT+vehicle, and MCT+BB (with doses of 10, 20, 30, and 40 mg/kg) groups. Three weeks after induction of PAH by MCT, treatment groups received daily intraperitoneal injections of vehicle or BB for 3 weeks. On Day 43, the right ventricular systolic pressure (RVSP, as an index of pulmonary arterial pressure) and the ratio of RV to LV+septum weight (as RV hypertrophy index, right ventricle hypertrophy [RHVI]) were measured. Inflammatory and oxidative stress indices and histopathology of the lungs were also assessed. RVSP (89.4 ± 8.2 vs. 23 ± 3.3), RVHI (0.63 ± 0.08 vs. 0.26 ± 0.04), and lung inflammatory cytokines TNF-α (2.03 ± 0.25 vs. 1.21 ± 0.3) and IL-6 (8.8 ± 0.59 vs. 6.3 ± 0.95) significantly increased in the MCT group compared to the control group. MCT also raised the level of Malondialdehyde (0.11 ± 0.01 vs. 0.09 ± 0.01) and diminished total antioxidant capacity (6.5 ± 0.51 vs. 8.3 ± 0.62), the activity of superoxide dismutase (1.19 ± 0.22 vs. 1.93 ± 0.2), glutathione peroxidase (0.02 ± 0.002 vs. 0.03 ± 0.005), catalase (2.1 ± 0.29 vs. 2.8 ± 0.20) and Bax/Bcl-2 ratio (0.41 ± 0.07 vs. 0.61 ± 0.09) in the lungs. Treatment with BB significantly recovered all of these alterations. BB ameliorated pulmonary vascular remodeling by decreasing inflammation and fibrosis and increasing apoptosis and antioxidant/oxidant balance. Therefore, this herbal derivative may be considered a therapeutic goal against PAH.

The role of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in the pulmonary vascular remodeling of pulmonary arterial hypertension in rats

The role of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in the pulmonary vascular remodeling of pulmonary arterial hypertension in rats

The role of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in the pulmonary vascular remodeling of pulmonary arterial hypertension in rats

The role of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in the pulmonary vascular remodeling of pulmonary arterial hypertension in rats

Participation of Leptin and Corticosterone in the Decrease in Infarct-Limiting Efficiency of Remote Postconditioning and in the Development of Arterial Hypertension in Metabolic Syndrome in Rats

We studied the effect of induced metabolic syndrome (MetS) on the effectiveness of the infarct-limiting effect of remote ischemic postconditioning (RP) in Wistar rats. The involvement of leptin and corticosterone in the formation of arterial hypertension (AH) and in reduction of the effectiveness of RP in MetS was also studied. MetS was induced by high-carbohydrate high-fat diet with replacement of drinking water with 20% fructose solution for 90 days. MetS simulation led to obesity, AH, impaired lipid and carbohydrate metabolism, hyperleptinemia, and moderate stress. All animals were subjected to 45-min coronary occlusion and 120-min reperfusion. In the RP groups, tourniquets were applied on the hind limbs in the area of the hip joint immediately after the end of ischemia (3 cycles consisting of 5-min ischemia and 5-min reperfusion). A direct correlation was found between the severity of AH in rats with MetS and the levels of corticosterone and leptin. In rats with MetS, the effectiveness of RP decreased: a direct correlation between the infarct size and serum content of leptin was revealed in rats with MetS+RP. Corticosterone seems to be one of the factors of AH development in rats with MetS.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat.

IntroductionCurrent 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.MethodsIn 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.ResultsWe 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-1β, 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.ConclusionOur studies show that notopterol exerts anti-inflammatory and anti-proliferative effects in the pulmonary arteries, which may contribute to prevention of PAH.

Celastrol attenuates the remodeling of pulmonary vascular and right ventricular in monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension is a progressive angio-proliferative disease associated with high morbidity and mortality rates. Although the histopathology of pulmonary arterial hypertension is well described, its therapeutic option remains unsatisfactory. This study investigated the effect of celastrol treatment on right ventricular dysfunction, remodeling, and pulmonary vascular remodeling in pulmonary arterial hypertension rats as well as its possible mechanisms. Pulmonary arterial hypertension was induced in male Sprague-Dawley rats by a single subcutaneously injection of monocrotaline. After daily delivery of celastrol (1 mg/kg) or vehicle via intraperitoneal injection for 4 weeks, the effects of celastrol on right ventricular function, fibrosis, and pulmonary vascular remodeling were assessed. The infiltration of macrophages, the expression of inflammatory cytokines, including MCP-1, IL-1β, IL-6, and IL-10, and the expression of NF-κB signaling pathway-associated proteins, IκBα, p-IKKα/β and p65 were further detected. Finally, the effect of celastrol on human pulmonary artery smooth cells proliferation under hypoxia was studied in vitro. Rats with pulmonary arterial hypertension had decreased right ventricular function, increased right ventricular fibrosis and pulmonary arteries with interstitial thickening and prominent media hypertrophy. Treatment with celastrol improved right ventricular function, attenuated right ventricular fibrosis and pulmonary vascular remodeling. Significantly decreased macrophage infiltration, reduced levels of pro-inflammatory cytokines, increased level of anti-inflammatory cytokine and inhibited NF-κB signaling pathway were observed in the lung tissues of rats treated with celastrol. Moreover, celastrol significantly suppressed the proliferation of human pulmonary artery smooth cells under hypoxia. We showed that in rats with pulmonary arterial hypertension, celastrol could improve right ventricular function, attenuate right ventricular and pulmonary vascular remodeling, and inhibit human pulmonary artery smooth cells proliferation under hypoxia. Suppression of the nuclear factor-κB (NF-κB) signaling pathway may be a part of the protective mechanism.

Study of possible sex features of ramipril and candesartan treatment under experimental arterial hypertension in rats

The article presents the results of a preclinical study of ramipril and candesartan in an experimental group of hypertensive rats of different sexes. Antihypertensive therapy was performed for 21 days. The drugs were administered daily in moderate therapeutic doses calculated for rats using the coefficient of species sensitivity. It was found that the course of experimental hypertension has gender differences, and in males, according to blood pressure, the level of NO metabolites is more pronounced. The use of ramipril from the group of ACE inhibitors and candesartan from the ARBs group in experimental hypertension in rats has gender differences. Ramipril is likely to be more effective in normalizing blood pressure and endothelial function in males than females. The use of candesartan did not show significant gender differences, but there was a tendency for females to be slightly more effective than males. Established gender differences in hypertension pharmacotherapy should be considered to optimize treatment.

The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.