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Haiying Chen, Hongli Yang, Hongmei Yue, Pádraig Michael Strappe, Peng Xia, Li Pan, Yingxin Zhang, Shoudong Chai, Shuangfeng Chen, Longle Ma, Lexin Wang
BACKGROUND: This study aimed to investigate the effect of bone marrow derived mesenchymal stem cells (rBMSCs) transduced with lentiviral vectors expressing endothelial nitric oxide synthase (eNOS) and/or a mutant caveolin-1(F92A-Cav1), on the pulmonary haemodynamics and structure in a rat model of pulmonary arterial hypertension (PAH). METHODS: Pulmonary arterial hypertension was induced with monocrotaline (MCT) in 60 adult male Wistar rats prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1, eNOS and/or F92A-Cav1...
September 9, 2016: Heart, Lung & Circulation
Natasha M Rogers, Maryam Sharifi-Sanjani, Mingyi Yao, Kedar Ghimire, Raquel Bienes-Martinez, Stephanie M Mutchler, Heather E Knupp, Jeffrey Baust, Enrico M Novelli, Mark Ross, Claudette St Croix, Johannes C Kutten, Caitlin A Czajka, John C Sembrat, Mauricio Rojas, David Labrousse-Arias, Timothy N Bachman, Rebecca R Vanderpool, Brian S Zuckerbraun, Hunter C Champion, Ana L Mora, Adam C Straub, Richard A Bilonick, Maria J Calzada, Jeffrey S Isenberg
AIMS: Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1(-/-) mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1-CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy. METHODS AND RESULTS: We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with (n=23) and without (n=16) PH. Compared to controls, lungs and distal PAs from PH patients showed induction of TSP1-CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA...
October 13, 2016: Cardiovascular Research
Pengwei Zhuang, Yingying Huang, Zhiqiang Lu, Zhen Yang, Liman Xu, Fengjiao Sun, Yanjun Zhang, Jinao Duan
Aconiti Lateralis Radix Praeparata (Fuzi) and Fritillariae Thunbergii bulbus (Beimu) have been widely used clinically to treat cardiopulmonary related diseases in China. However, according to the classic rules of traditional Chinese medicine, Fuzi and Beimu should be prohibited to use as a combination for their incompatibility. Therefore, it is critical to elucidate the paradox on the use of Fuzi and Beimu combination therapy. Monocrotaline-induced pulmonary hypertension rats were treated with either Fuzi, Beimu, or their combination at different stages of PH...
October 14, 2016: Scientific Reports
Aya Yamamura
 Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca(2+) channel blockers are only effective in very few patients with IPAH (<10%)...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Chen Liu, Xiao-Min Jiang, Juan Zhang, Bing Li, Jing Li, Du-Jiang Xie, Zuo-Ying Hu
BACKGROUND: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. METHODS: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19)...
October 10, 2016: BMC Cardiovascular Disorders
Erica R Pursell, Daniela Vélez-Rendón, Daniela Valdez-Jasso
In a MCT induced-PAH rat animal model, the dynamic stress-strain relation was investigated in the circumferential and axial direction using a linear elastic response model within the quasi-linear viscoelasticity theory framework. Right and left pulmonary arterial segments (RPA, LPA) were mechanically tested in a tubular biaxial device at the early stage (1 week post-MCT treatment) and at the advanced stage of the disease (4 weeks post-MCT treatment). The vessels were tested circumferentially at the in vivo axial length with matching in vivo measured pressure ranges...
September 29, 2016: Journal of Biomechanical Engineering
Rohan Varshney, Quaisar Ali, Chengxiang Wu, Zhongjie Sun
The objective of this study is to investigate whether stem cell delivery of secreted Klotho (SKL), an aging-suppressor protein, attenuates monocrotaline-induced pulmonary vascular dysfunction and remodeling. Overexpression of SKL in mesenchymal stem cells (MSCs) was achieved by transfecting MSCs with lentiviral vectors expressing SKL-green fluorescent protein (GFP). Four groups of rats were treated with monocrotaline, whereas an additional group was given saline (control). Three days later, 4 monocrotaline-treated groups received intravenous delivery of nontransfected MSCs, MSC-GFP, MSC-SKL-GFP, and PBS, respectively...
November 2016: Hypertension
Zhigang Hong, Kuang-Hueih Chen, Asish Dasgupta, Francois Potus, Kimberly Dunham-Snary, Sebastien Bonnet, Lian Tian, Jennifer Fu, Sandra Breuils-Bonnet, Steeve Provencher, Danchen Wu, Jeffrey Mewburn, Mark L Ormiston, Stephen L Archer
RATIONALE: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cells (PASMC) proliferation, migration, and apoptosis-resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis and mitochondrial fission. OBJECTIVES: To determine how changes in mitochondrial calcium uniporter complex (MCUC) function influence mitochondrial dynamics and contribute to PAH's cancer-like phenotype...
September 20, 2016: American Journal of Respiratory and Critical Care Medicine
Na Qin, Wei Yang, Dongxu Feng, Xinwen Wang, Muyao Qi, Tianxin Du, Hongzhi Sun, Shufang Wu
BACKGROUND: Ginsenosides have been shown to exert beneficial pharmacological effects on the central nervous, cardiovascular, and endocrine systems. We sought to determine whether total ginsenosides (TG) inhibit monocrotaline (MCT)-induced pulmonary hypertension and to elucidate the underlying mechanism. METHODS: MCT-intoxicated rats were treated with gradient doses of TG, with or without N (G)-nitro-l-arginine methyl ester. The levels of molecules involving the regulation of nitric oxide and mitogen-activated protein kinase pathways were determined...
July 2016: Journal of Ginseng Research
Jeong Hyun Lee, Byung Kil Park, Kwang-Seok Oh, Kyu Yang Yi, Chae Jo Lim, Ho Won Seo, Byung Ho Lee
The pathophysiological implications of binding of urotensin II (U-II) to urotensin II receptor (UT) in pulmonary arterial hypertension (PAH) have been proposed recently. Besides high expression of U-II in experimental models and patients with PAH, U-II has been shown to increase proliferation of pulmonary vascular smooth muscle cells and inflammatory responses, which were critical for PAH pathophysiology. However, the direct role of the urotensinergic system in the pathogenesis of PAH is yet to be understood...
September 6, 2016: International Immunopharmacology
Azin Jafari, Sven Wehner, Jörg C Kalff, Steffen Manekeller
PURPOSE: In recent years, multimodal treatment approaches have led to an increased median survival time of patients with colorectal liver metastases. In particular, this results from new perioperative chemotherapy regimens, which in turn are accompanied by an increased risk of perioperative bleeding and/or liver failure due to the hepatotoxic side effects. Nineteen to 58 % of patients treated with oxaliplatin develop sinusoidal obstruction syndrome (SOS). The influence of preexisting SOS on liver surgery remains controversial...
September 1, 2016: Langenbeck's Archives of Surgery
Mei-Yueh Lee, Kun-Bow Tsai, Jong-Hau Hsu, Shyi-Jang Shin, Jiunn-Ren Wu, Jwu-Lai Yeh
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro...
2016: Scientific Reports
E L Peters, C Offringa, D Kos, W J Van der Laarse, R T Jaspers
A major problem in chronic heart failure is the inability of hypertrophied cardiomyocytes to maintain the required power output. A Hill-type oxygen diffusion model predicts that oxygen supply is limiting in hypertrophied cardiomyocytes at maximal rates of oxygen consumption and that this limitation can be reduced by increasing the myoglobin (Mb) concentration. We explored how cardiac hypertrophy, oxidative capacity, and Mb expression in right ventricular cardiomyocytes are regulated at the transcriptional and translational levels in an early stage of experimental pulmonary hypertension, in order to identify targets to improve the oxygen supply/demand ratio...
October 2016: Pflügers Archiv: European Journal of Physiology
Thomas Bertero, William M Oldham, Katherine A Cottrill, Sabrina Pisano, Rebecca R Vanderpool, Qiujun Yu, Jingsi Zhao, Yiyin Tai, Ying Tang, Ying-Yi Zhang, Sofiya Rehman, Masataka Sugahara, Zhi Qi, John Gorcsan, Sara O Vargas, Rajan Saggar, Rajeev Saggar, W Dean Wallace, David J Ross, Kathleen J Haley, Aaron B Waxman, Victoria N Parikh, Teresa De Marco, Priscilla Y Hsue, Alison Morris, Marc A Simon, Karen A Norris, Cedric Gaggioli, Joseph Loscalzo, Joshua Fessel, Stephen Y Chan
Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis...
September 1, 2016: Journal of Clinical Investigation
Feng Chen, Xueyi Li, Emily Aquadro, Stephen Haigh, Jiliang Zhou, David W Stepp, Neal L Weintraub, Scott A Barman, David J R Fulton
Excessive levels of reactive oxygen species (ROS) and increased expression of NADPH oxidases (Nox) have been proposed to contribute to pulmonary artery hypertension (PAH) and other cardiovascular diseases (CVD). Nox enzymes are major sources of ROS but the mechanisms regulating changes in Nox expression in disease states remain poorly understood. Epigenetics encompasses a number of mechanisms that cells employ to regulate the ability to read and transcribe DNA. Histone acetylation is a prominent example of an epigenetic mechanism regulating the expression of numerous genes by altering chromatin accessibility...
August 3, 2016: Free Radical Biology & Medicine
Jie Yin, Shuling You, Nannan Li, Shouhai Jiao, Hesheng Hu, Mei Xue, Ye Wang, Wenjuan Cheng, Ju Liu, Min Xu, Suhua Yan, Xiaolu Li
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease associated with high morbidity and mortality rates. However, the exact regulatory mechanism of PAH is unknown. Although coupling factor 6 (CF6) is known to function as a repressor, its role in PAH has not been explored. Here, we investigated the involvement of endogenous CF6 in the development of PAH. METHODS: PAH was induced with monocrotaline (MCT), as demonstrated by significant increases in pulmonary artery pressure and vessel wall thickness...
2016: Respiratory Research
Magdalena Jasińska-Stroschein, Jacek Owczarek, Urszula Sołtysiak, Daria Orszulak-Michalak
INTRODUCTION: It remains controversial whether statins have a beneficial effect on pulmonary arterial hypertension (PAH). This study is intended to evaluate whether statin, co-administered with Rho-kinase inhibitor, could enhance its efficacy. Although Rho-kinase inhibitors, including fasudil, have been reported to improve pulmonary hypertension in experimental and clinical studies, the combination of these agents has not been tested in the treatment of pulmonary hypertension (PH). MATERIAL AND METHODS: The effects of such a regimen on hemodynamics, right ventricle hypertrophy, and Rho-associated protein kinase (ROCK) activity in experimental monocrotaline (MCT)-induced pulmonary hypertension were examined...
August 1, 2016: Archives of Medical Science: AMS
Mohamed Alaa, Mahmoud Abdellatif, Marta Tavares-Silva, José Oliveira-Pinto, Lucas Lopes, Sara Leite, Adelino F Leite-Moreira, André P Lourenço
Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI)...
October 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Guo-Kun Wang, Song-Hua Li, Zhi-Min Zhao, Su-Xuan Liu, Guan-Xin Zhang, Fan Yang, Yang Wang, Feng Wu, Xian-Xian Zhao, Zhi-Yun Xu
While the molecular chaperone heat shock protein 90 (HSP90) is involved in a multitude of physiological and pathological processes, its role relating to pulmonary arterial hypertension (PAH) remains unclear. In the present study, we investigated the effect in which HSP90 improves pulmonary arteriole remodeling, and explored the therapeutic utility of targeting HSP90 as therapeutic drug for PAH. By Elisa and immunohistochemistry, HSP90 was found to be increased in both plasma and membrane walls of pulmonary arterioles from PAH patients...
July 26, 2016: Oncotarget
Haiying Chen, Hongli Yang, Chong Xu, Hongmei Yue, Peng Xia, Pádraig Michael Strappe, Lei Wang, Li Pan, Wenqiang Tang, Shuangfeng Chen, Lexin Wang
BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow-derived mesenchymal stem cells (rBMSCs) transduced with a mutant caveolin-1(F92A-Cav1) could enhance endothelial nitric oxide synthase (eNOS) activity and improve pulmonary vascular remodeling, but the potential mechanism is not yet fully explored. The present study was to investigate the gene expression profile upon rBMSCs/F92A-Cav1delivered to PAH rat to evaluate the role of F92A-Cav1 in its regulation...
June 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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