Effects of Crocin on CCL2/CCR2 Inflammatory Pathway in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

2021 ◽  
pp. 1-19
Author(s):  
Yanling Sheng ◽  
Xiaowei Gong ◽  
Jing Zhao ◽  
Yan Liu ◽  
Yadong Yuan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stress Responses ◽  
Systolic Pressure ◽  
Pathological Feature ◽  
Arterial Remodeling ◽  
Inflammatory Pathway ◽  
Ventricular Systolic Pressure ◽  
Rat Models ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary disease, in which pulmonary arterial remodeling is regarded as the prominent pathological feature. So far, the mechanism of PAH is still unclear, so its treatment remains a challenge. However, inflammation plays an important part in the occurrence and progression of PAH. It is well known that crocin has anti-inflammatory properties, so we investigated whether crocin could be a potential drug for the treatment of PAH rat models. Rats injected subcutaneously with monocrotaline (MCT) were treated with crocin via a gastric tube daily for four weeks. The results showed that crocin treatment significantly reduced the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) in the PAH rat models. Moreover, crocin treatment reduced the proliferation of pulmonary arteriole smooth muscle cells (PASMCs). In addition, crocin treatment not only relieved inflammatory cell infiltration and collagen fiber hyperplasia in the lung and right ventricle, but also decreased the expression of the CCL2/CCR2 inflammatory pathway in the lung of PAH rat models. Furthermore, crocin treatment reduced the inflammatory cytokines and oxidative stress responses. In summary, crocin may play a protective role in MCT-induced PAH rats by alleviating inflammatory response, improving pulmonary arterial remodeling, and preventing PAH. Therefore, crocin as a new treatment for PAH may be quite worthy of consideration.

scholarly journals Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1787-1798
Author(s):  
Fangcheng Luo ◽  
Liangmiao Wu ◽  
Guoqing Xie ◽  
FangFang Gao ◽  
Zhixiang Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pulmonary Vascular Disease ◽  
Arterial Remodeling ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Dual Functional ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare, progressive pulmonary vascular disease with limited therapeutic options. Pulmonary circulation resistance, pulmonary vascular remodeling, and over-activated NMDARs (N-methyl-d-aspartate receptors) play vital roles in the pathogenesis of PAH. In the present study, we aimed to evaluate the efficacy and molecular mechanism of MN-08, a dual-functional memantine nitrate derivative, in experimental animal models of PAH. MN-08 showed a high degree of accumulation in the lungs and dilated pulmonary arterial rings ex vivo by releasing nitric oxide. MN-08 did not lower systemic blood pressure. MN-08 attenuated right ventricular systolic pressure and right ventricular hypertrophy, inhibited pulmonary arterial remodeling, alleviated glutamate-NMDARs dysregulation, and improved survival rates in monocrotaline-induced PAH rats. More importantly, the therapeutic benefit of MN-08 for PAH was greater than that of sildenafil. Moreover, MN-08 can reduce right ventricular systolic pressure in U46619-induced acute PAH rats. Mechanistically, MN-08 suppressed proliferation of pulmonary arterial smooth muscle cells exposed to human platelet-derived growth factor-BB by regulating the cell cycle and expression of NMDAR1, AKT (serine/threonine kinase Akt), and ERK (extracellular signal-regulated kinase) 1/2. In conclusion, our studies demonstrated that MN-08 may be a promising therapeutic agent for PAH.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

scholarly journals Leptin signalling system as a target for pulmonary arterial hypertension therapy

2015 ◽  
Vol 45 (4) ◽  
pp. 1066-1080 ◽  
Author(s):  
Alice Huertas ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Morane Le Hiress ◽  
Carole Phan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Perivascular Inflammation ◽  
Current Therapies ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Pulmonary Arterial Hypertension Therapy

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

scholarly journals Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Takanori Watanabe ◽  
Mariko Ishikawa ◽  
Kohtaro Abe ◽  
Tomohito Ishikawa ◽  
Satomi Imakiire ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Increase ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

scholarly journals EXPRESS: Carfilzomib-associated Pulmonary Arterial Hypertension in Multiple Myeloma

2021 ◽  
pp. 204589402110493
Author(s):  
Jenny Yang ◽  
Taylor Buckstaff ◽  
Anna Narezkina ◽  
Timothy Fernandes
Keyword(s):  
Multiple Myeloma ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
New Drugs ◽  
Heart Catheterization ◽  
Drug Induced ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early, however extended follow up is essential.

scholarly journals Rutin Reverses Abnormal Autophagy in Hypoxic Pulmonary Arterial Hypertension via Regulation of Mitofusin 1

2021 ◽  
Author(s):  
Ming-xue Huang ◽  
Man Wang ◽  
Yu-wei Song ◽  
Yan Song ◽  
Ling Jing
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Exposure Period ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
Protective Effects ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Mitofusin 1

Abstract Background:Recently, rutin, a citrus flavonoid occurring in many plants, has been found to be beneficial in preventing hypoxia-induced pulmonary arterial smooth muscle cells (PASMCs) from proliferating via scavenged reactive oxygen species (ROS). However, rutin’s underlying mechanism of action against PASMCs in the context of hypoxia is still unclear. Autophagy, the main intracellular degradation and recycling process, exerts a critical adaptive effect on the pathological angiogenesis associated with hypoxic pulmonary arterial hypertension (HPAH) by removing damaged mitochondria and regulating ROS production and cell proliferation. It would be useful to identify the role of rutin and its interaction with autophagy in exerting protective effects against HPAH.Methods:We chose 21 SD rats and randomly and equally divided them into three groups of normoxia, hypoxia, and hypoxia + rutin. At the end of the exposure period, we measured the right ventricular systolic pressure (RVSP), the weight of right ventricle (RV), and the ratio of RV weight to left ventricular (LV) weight plus septum (RV/LV+S) of each rat. PASMCs of the three groups of rats were isolated and cultured, and the effect of rutin on autophagy-related protein expression under hypoxia was analyzed using immunofluorescence analysis, transmission electron microscopy, western blot (WB) analysis, and siRNA design and transfection.Results:We found RVSP, RV/LV+S, and pulmonary artery wall thickness were reduced by rutin in the pulmonary arterial hypertension (PAH) animal model. WB results showed that rutin regulated expression of autophagy-related proteins. Moreover, rutin downregulated Mitofusin 1 (Mfn1) over-expression induced by hypoxia. But when Mfn1 was silenced, there was little difference in the expressions of beclin-1 (BECN-1), and other marker proteins with or without rutin.Conclusions:Rutin suppressed the abnormal autophagy of hypoxia-induced PASMCs via the regulation of the target, Mfn1. This revealed the protective effect of rutin on vascular remodeling caused by hypoxia and demonstrated how rutin could slow down the development of HPAH.

Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

2021 ◽  
pp. 2000653
Author(s):  
Hélène Le Ribeuz ◽  
Lucie To ◽  
Maria-Rosa Ghigna ◽  
Clémence Martin ◽  
Chandran Nagaraj ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Vascular Cell ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

IntroductionA reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.Aim and objectivesWe aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and resultsRT-Q-PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myograph on human, pig and rat PAs, we demonstrated that CFTR activation induces PAs relaxation. CFTR-mediated PA relaxation was reduced in PAs from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularization. Pathologic assessment of lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.ConclusionsCFTR expression is strongly decreased in PA smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces PA relaxation.

Abstract 13972: Dexmedetomidine Ameliorates Monocrotaline Induced Pulmonary Arterial Hypertension in Rats

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yusuke Kajikawa ◽  
Susumu Hosokawa ◽  
Kenji Wakabayashi ◽  
Yasuhiro Maejima ◽  
Mitsuaki Isobe ◽  
...  
Keyword(s):  
Survival Rate ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Inflammatory Responses ◽  
Systolic Pressure ◽  
Sprague Dawley ◽  
Apoptosis Resistance ◽  
Ventricular Systolic Pressure ◽  
Significant Difference ◽  
Pulmonary Arterial

[Introduction] Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Dexmedetomidine (DEX) is a selective α2-aderenergic receptor agonist that is used for sedation in clinical practice. It has been reported that DEX inhibits inflammatory responses through cytokines, such as TNF-alpha, IL-6. Furthermore other reports show that G-protein-coupled receptors (GPCRs) are regulated by β-arrestins, which are also involved with inflammation. [Hypothesis] DEX ameliorates monocrotaline (MCT)-induced PAH in rats by its anti-inflammatory effect. [Methods] We treated 6 weeks-old male Sprague-Dawley rats with a single 60mg/kg intraperitoneal injection of MCT. After 14 days of injection, one group of rats was started to administer dexmedetomidine (dose: 2μg/kg/hour, MCT+DEX group) continuously using osmotic pumps, the other group was not treated with DEX (MCT group). We performed physiological examination and cardiac catheterization to measure right ventricular systolic pressure (RVSP) at day 23. [Results] Both RVSP and survival rate of rats in MCT+DEX group markedly improved compared with those in MCT group (RVSP; 38mmHg±11mmHg vs 91mmHg±6mmHg, survival rate; 42% vs 0% at day 30). In histological analysis, DEX reduced the medial hypertrophy of pulmonary arterioles, and decreased phosphorylated-NF-kB p65 (p-p65) positive PASMCs in MCT+DEX group compared with those of MCT group. In addition, DEX suppressed PASMCs proliferation with PCNA staining, and induced apoptosis of PASMCs with TUNEL assay. Then we examined the involvement of β-arrestins in PAH. It showed that βarrestin1 expressions reduced in MCT group compared with that of MCT+DEX group with western blotting and immunohistochemistry. However β-arrestin2 expressions had no significant difference between the two groups. [Conclusions] DEX ameliorates MCT-induced PAH in rats, one of the mechanism of which may be NF-kB inhibition through β-arrestin1. DEX can be a new therapeutic tool for PAH.

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