Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Xiao, Rui; Su, Yuan; Tian, Feng; Sun, Mengxiang; Liu, Bingxun; Zhang, Jiwei; Lu, Yang; Li, Jiansha; Wang, Tao; Zhu, Liping; Hu, Qinghua

doi:10.1161/jaha.116.004865

Cited by 43 publications

(51 citation statements)

References 61 publications

(176 reference statements)

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“…Consistent and pathognomonic results were found for the vascular bed of the lungs for all groups treated with the PAH phenotype [30,31]. RES had a minimal effect in reversing them, other authors found that RES had a limited antiremodeling effect on the lungs, and this effect was limited to the medial layer of the pulmonary trunk and did not impact the heart wall structure [13].…”

Section: Discussionsupporting

confidence: 67%

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Vázquez‐Garza

Bernal‐Ramírez

Jerjes‐Sánchez

et al. 2020

Oxidative Medicine and Cellular Longevity

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Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.

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Section: Discussionsupporting

confidence: 67%

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Vázquez‐Garza

Bernal‐Ramírez

Jerjes‐Sánchez

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…MCT injected animal have been extensively used to study pathogenesis and therapeutic interventions of PAH 6,7 . The MCT animal model of PAH has been reported to be characterised by increased pulmonary artery medial wall thickness, vasculitis, and RV hypertrophy which ultimately might lead to increased mortality 6,7 . Corroborating previous literature we also observed after 3 weeks of MCT injection rats developed significant increase in RVSP, medial wall thickness of pulmonary arteries (25-200 µm) and RV hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous researchers have established that a single dose of MCT (intraperitonealor subcutaneous) induces PAH in animals by pulmonary endothelial damage, medial hypertrophy of the pulmonary arteries, and subsequently right ventricular remodelling 6 . Recent evidences suggest MCT induces endothelial dysfunction and consequent pulmonary arterial hypertension, by binding to extra cellular calcium sensing receptor (CaSR) 7 . Calcium (Ca 2+ ) channel pathway has been previously related to play a key role in vasoconstriction and remodelling of pulmonary vessels.…”

Section: Introductionmentioning

confidence: 99%

“…Calcium (Ca 2+ ) channel pathway has been previously related to play a key role in vasoconstriction and remodelling of pulmonary vessels. Intracellular Ca 2+ [Ca 2+ ] i acts as a secondary messenger and its imbalance can greatly influence pathophysiology of PAH by inducing PASMC proliferation and P-EC instability 7 . Calcium channel blockers (CCBs), which are a class of drugs that avert entry of Ca 2+ into cardio myocytes, PASMC and P-EC, hence preclude contractility of heart and constriction of pulmonary arteries (PA) [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

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Ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate Prevents Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

et al. 2017

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<p>Therapies to prevent onset and progression of pulmonary arterial pressure are not very effective yet. This study was designed to investigate the effects of a novel dihydropyrimidinone, ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM) on pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). For the same purpose, rats were injected intraperitoneally (i.p.) a single dose (60 mg/kg) of MCT which led to development of PAH in 21 days. MCT insult caused high mortality, pulmonary vascular and parenchymal remodelling. Since the course of PAH pathogenesis is characterised by an early onset and progression phases, H-DHPM was administered i.p. at 30 mg/kg dosage in MCT pre-injected animals either from day 0 through day 21 or day 14 though day 21 of MCT injection in two separate treatment groups. H-DHPM significantly improved survival, prevented remodelling of pulmonary vasculature and parenchyma and subsequently ameliorated PAH pathogenesis. Moreover, we observed significant decrease in right ventricle hypertrophy, measured by wet weight of right ventricle (RV) divided by wet weight of left ventricle plus septum (LV+S), in H-DHPM treated groups as compared to MCT injected animals. These findings suggest H-DHPM not only prevented development of PAH but also treated the PAH pathogenesis in progressive phase. In conclusion, our data determines H-DHPM, might be a future drug for the prevention of PAH.</p>

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“…PASMCs and PAECs were isolated using the methods according to previous reports (32, 47, 48). PASMCs and PAECs were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 20% FBS for 48h, respectively (32, 49).…”

Section: Methodsmentioning

confidence: 99%

Transcriptome-wide map of m⁶A circRNAs identified in hypoxic pulmonary hypertension rat model

Zhou

et al. 2019

Preprint

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32Hypoxic pulmonary hypertension (HPH) is a lethal disease. CircRNAs and m 6 A 33 circRNAs have been reported to be associated with cancer progression, but the 34 expression profiling of m 6 A circRNAs has not been identified in HPH. This study was 35 to investigate the transcriptome-wide map of m 6 A circRNAs in HPH. In this study, 36 hypoxia-induced PH rat model was established. Total RNA was extracted and purified 37 from lungs of rats, then circRNAs were detected and annotated by RNA-seq analysis. 38 m 6 A RNA Immunoprecipitation (MeRIP) was performed following rRNA depletion, 39 and RNA-seq library was constructed. CircRNA-miRNA-mRNA co-expression 40 network was also constructed. In vitro, total m 6 A was measured. m 6 A circXpo6 and 41 m 6 A circTmtc3 were detected in pulmonary artery smooth muscle cells (PASMCs) and 42 pulmonary artery endothelial cells (PAECs) exposed to 21% O 2 and 1% O 2 for 48 h, 43 respectively. m 6 A abundance in 166 circRNAs was significantly upregulated and m 6 A 44 abundance in 191 circRNAs was significantly downregulated in lungs of HPH rats. 45 m 6 A abundance in circRNAs was significantly reduced in hypoxia in vitro. m 6 A 46 circRNAs were mainly derived from single exons of protein-coding genes. m 6 A 47 influenced the circRNA-miRNA-mRNA co-expression network in hypoxia. m 6 A 48 circXpo6 and m 6 A circTmtc3 were downregulated in hypoxia. In general, our study 49 firstly identified the transcriptome-wide map of m 6 A circRNAs in HPH. m 6 A level in 50 circRNAs was decreased in lungs of HPH rats and in PASMCs and PAECs exposed to 51 hypoxia. Downregulated or upregulated m 6 A level influenced circRNA-miRNA-52 mRNA co-expression network in HPH. Moreover, we firstly identified two 53 downregulated m 6 A circRNAs in HPH: circXpo6 and circTmtc3. We suggested that 54 m 6 A circRNAs may be used as a potential diagnostic marker or therapy target in the 55 future.56 57 58 59 60 3 61 62 Author summary 63 HPH is a disease with great morbidity and mortality. It is often caused by chronic 64 hypoxic lung diseases, such as chronic obstructive pulmonary disease and interstitial 65 lung diseases. It lacks effective therapy methods so far. CircRNAs are a type of non-66 coding RNAs and can be used as biomarkers because they are differentially enriched in 67 specific cell types or tissues and not easily degraded. m 6 A is identified as the most 68 universal modification on non-coding RNAs in eukaryotes. CircRNAs can be modified 69 by m 6 A. m 6 A circRNAs in HPH is not well understood yet. Here we identify the 70 transcriptome-wide map of m 6 A circRNAs in HPH. We elucidate that m 6 A level in 71circRNAs is decreased in lungs of HPH rats and in PASMCs and PAECs exposed to 72 hypoxia. We find that downregulated or upregulated m 6 A level influences circRNA-73 miRNA-mRNA co-expression network in HPH. Moreover, we are the first to identify 74 two downregulated m 6 A circRNAs in HPH: circXpo6 and circTmtc3. We suggest that 75 m 6 A circRNAs may be used as a potential diagnostic marker or thera...

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Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Cited by 43 publications

References 61 publications

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate Prevents Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Transcriptome-wide map of m⁶A circRNAs identified in hypoxic pulmonary hypertension rat model

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Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium–Sensing Receptor

Cited by 43 publications

References 61 publications

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature

Ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate Prevents Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Transcriptome-wide map of m6A circRNAs identified in hypoxic pulmonary hypertension rat model

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Transcriptome-wide map of m⁶A circRNAs identified in hypoxic pulmonary hypertension rat model