Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Cheng, Yusheng; Yu, Min; Xu, Jian; He, Mengyu; Wang, Hong; Kong, Hui; Xie, Weiping

doi:10.1186/s12890-018-0700-y

Cited by 19 publications

(10 citation statements)

References 39 publications

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“…We previously reported rare inherited LGD or D-Mis variants in CHD risk genes NOTCH1 ( n = 5), PTPN11 ( n = 1), and RAF1 ( n = 2) carried by APAH-CHD cases [ 18 ]. Specific inhibition of the protein encoded by PTPN11 (SHP2) [ 97 ], and induction of mir-204 which negatively targets SHP2 [ 98 ], improved right ventricular function in the monocrotaline rat model of PAH, suggesting a more general role of PTPN11 in PAH.…”

Section: Discussionmentioning

confidence: 99%

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

et al. 2021

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Background Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

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Section: Discussionmentioning

confidence: 99%

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

et al. 2021

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“…In addition, pulmonary artery remodeling, including wall thickening, muscularization, and fibrosis of the outer membrane in pulmonary artery, eventually leading to right heart failure, was also an important pathological feature of PAH (Cajigas & Awdish, 2016; Hoette, Jardim, & Souza, 2010; Stenmark, Fagan, & Frid, 2006). In previous researches, the indexes of WT%, WA%, and infiltration of inflammatory were used to assess pulmonary artery remodeling (Cheng et al, 2018; Davies et al, 2012; Pickworth et al, 2017; Wu, Hao, et al, 2017; Zhang, Chang, Zhao, et al, 2019), and CSA of cardiomyocyte was used to assess right ventricular hypertrophy (Chen, Shen, et al, 2019; Chen, Wang, et al, 2019). In the current study, H&E staining results revealed that isorhamnetin not only reduced the abnormal increase of MCT‐induced WT% and WA% and CSA but also improved MCT‐induced pulmonary arterial wall thickness, increased luminal stenosis wall, and infiltration of inflammatory cells in rats.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

Chang

Wang

Jing

et al. 2020

Phytotherapy Research

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Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti-proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF-α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT-induced PAH in rats. In vitro, isorhamnetin suppressed TNF-α-induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF-α and IL-6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p-smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT-induced PAH in rats and inhibited TNF-α-induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.

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“…We previously-reported rare inherited LGD or D-Mis variants in CHD risk genes NOTCH1 (n=5), PTPN11 (n=1) and RAF1 (n=2) carried by APAH-CHD cases (17). Specific inhibition of the protein encoded by PTPN11 (SHP2) (74), and induction of mir-204 which negatively targets SHP2 (75. ), improved right ventricular function in the monocrotaline rat model of PAH, suggesting a more general role of PTPN11 in PAH.…”

Section: While Effects Ofmentioning

confidence: 99%

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

Zhu

Swietlik

Welch

et al. 2020

Preprint

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Background -Group 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent highthroughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases. Methods-To identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource -Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzed de novo variants in 124 pediatric trios.Results -Seven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (FBLN2, fibulin 2; PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene, ACVRL1, showed association with APAH. Predicted deleterious de novo variants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carrying de novo variants have plausible roles in lung/heart development.Conclusions -Rare variant analysis of a large international consortium identifies two new candidate genes -FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained by de novo variants.

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Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats

Cited by 19 publications

References 39 publications

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH

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