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https://www.readbyqxmd.com/read/29901088/fasudil-preserves-lung-endothelial-function-and-reduces-pulmonary-vascular-remodeling-in-a-rat-model-of-end%C3%A2-stage-pulmonary-hypertension-with-left-heart-disease
#1
Rulin Zhuang, Jinfu Wu, Fang Lin, Lu Han, Xiaoting Liang, Qingshu Meng, Yuyu Jiang, Zhulin Wang, Aixue Yue, Yuying Gu, Huimin Fan, Xiaohui Zhou, Zhongmin Liu
Pulmonary hypertension (PH) due to left heart disease (LHD) is a common condition associated with significant morbidity. It contributes to the elevation of pulmonary vascular resistance and mean pulmonary pressure, eventually leading to heart failure and even mortality. The present study aimed to explore the potential efficacy of late and long‑term treatment with a Rho‑kinase (ROCK) signaling inhibitor, namely fasudil, in a rat model of end‑stage PH‑LHD. The PH‑LHD model was established by supracoronary aortic banding, and the effect of fasudil treatment on the progression of PH‑LHD was monitored...
June 13, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29785232/effects-of-fasudil-on-patients-with-pulmonary-hypertension-associated-with-left-ventricular-heart-failure-with-preserved-ejection-fraction-a-prospective-intervention-study
#2
Xiang Zhang, Xueming Zhang, Saihua Wang, Jun Luo, Zhihong Zhao, Changzhu Zheng, Jieyan Shen
Background: Pulmonary hypertension due to left ventricular heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly medical problem. The aim of the study was to evaluate the clinical efficacy of fasudil on PH-HFpEF elderly patients and to figure out the subtype of PH-HFpEF which may be the therapeutic object of fasudil. Method: 58 PH-HFpEF elderly patients were enrolled. Patients were diagnosed with passive pulmonary hypertension (PPH) or reactive pulmonary hypertension (RPH) by right heart catheterization and all receiving Rho kinase inhibitor fasudil for 2 weeks...
2018: Canadian Respiratory Journal: Journal of the Canadian Thoracic Society
https://www.readbyqxmd.com/read/29756460/inhaled-fasudil-lacks-pulmonary-selectivity-in-thromboxane-induced-acute-pulmonary-hypertension-in-newborn-lambs
#3
Shawn F L Hanson, Michael H Terry, Dafne T Moretta, Gordon G Power, Sean M Wilson, Farzana Alam, Fakhrul Ahsan, Arlin B Blood, Paresh C Giri
INTRODUCTION: Pulmonary hypertension (PH) is a potentially deadly disease for infants and adults with few existing medical interventions and no cure. In PH, increased blood pressure in the pulmonary artery eventually leads to heart failure. Fasudil, an antagonist of Rho-kinase, causes vasodilation leading to decreased systemic artery pressure and pulmonary artery pressure (PAP). This study compared the effects of fasudil administered as either an intravenous infusion or inhaled aerosol in newborn lambs...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29744294/synergistic-effects-of-hmg-coa-reductase-inhibitor-and-angiotensin-ii-receptor-blocker-on-load-induced-heart-failure
#4
Yusuke Ito, Yasuhiro Maejima, Natsuko Tamura, Yuka Shiheido-Watanabe, Masanori Konishi, Takashi Ashikaga, Kenzo Hirao, Mitsuaki Isobe
5-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure (HF), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker (ARB) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan (LOS)] and statin [simvastatin (SIM)] on cardiac function in rats and mice with load-induced HF. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS, SIM, or LOS + SIM for 8 weeks...
May 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29659121/glucagon-like-peptide-1-ameliorates-cardiac-lipotoxicity-in-diabetic-cardiomyopathy-via-the-ppar%C3%AE-pathway
#5
Lujin Wu, Ke Wang, Wei Wang, Zheng Wen, Peihua Wang, Lei Liu, Dao Wen Wang
Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks...
April 16, 2018: Aging Cell
https://www.readbyqxmd.com/read/29527586/rho-kinase-signaling-and-cardiac-physiology
#6
Yuan Dai, Weijia Luo, Jiang Chang
Rho kinases (ROCKs) are the first discovered RhoA effectors that are now widely known for their effects on actin organization. Recent studies have shown that ROCKs play important roles in cardiac physiology. Abnormal activation of ROCKs participate in multiple cardiovascular pathological processes, including cardiac hypertrophy, apoptosis, fibrosis, systemic hypertension, and pulmonary hypertension. ROCK inhibitors, fasudil and statins, have shown beneficial cardiovascular effects in many animal studies, clinical trials, and applications...
February 2018: Current Opinion in Physiology
https://www.readbyqxmd.com/read/29485964/expression-of-rho-kinase-and-its-mechanism-in-the-left-atrial-appendage-in-patients-with-atrial-fibrillation
#7
Yongqing Chen, Fangju Su, Juanping Han, Piqi Jiao, Wenyun Guo
To study the expression of Rho kinase (Rho associated coil forming protein kinase-1, ROCK-1) and its substrate myosin phosphatase target subunit 1 (myosin phosphatase target subunit-1, MYPT-1), connexin 40 (Cx40) and connexin 43 (Cx43) in the left atrial appendage of patients with atrial fibrillation, and explore the role of ROCK signaling pathway in patients with atrial fibrillation and its underlying mechanism. Methods: 40 patients undergoing open heart surgery were divided into two groups; atrial fibrillation group (AF group) and sinus rhythm group (SR group)...
February 19, 2018: Heart Surgery Forum
https://www.readbyqxmd.com/read/29451818/overexpression-of-heart-specific-small-subunit-of-myosin-light-chain-phosphatase-results-in-heart-failure-and-conduction-disturbance
#8
Takuro Arimura, Antoine Muchir, Masayoshi Kuwahara, Sachio Morimoto, Taisuke Ishikawa, Cheng-Kun Du, Dong-Yun Zhan, Shu Nakao, Noboru Machida, Ryo Tanaka, Yoshihisa Yamane, Takeharu Hayashi, Akinori Kimura
Mutations in genes encoding components of sarcomere cause cardiomyopathy, which is often associated with abnormal Ca2+ sensitivity of muscle contraction. We previously showed that a heart-specific myosin light chain phosphatase small subunit, hHS-M21 , increases the Ca2+ -sensitivity of muscle contraction. The aim of this study was to investigate the function of hHS-M21 in vivo and the causative role of abnormal Ca2+ sensitivity in cardiomyopathy. We generated transgenic (Tg) mice with cardiac-specific overexpression of hHS-M21 ...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29394331/vascular-smooth-muscle-contraction-in-hypertension
#9
Rhian M Touyz, Rheure Alves-Lopes, Francisco J Rios, Livia L Camargo, Aikaterini Anagnostopoulou, Anders Arner, Augusto C Montezano
Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function...
March 15, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29353861/neuroprotection-mediated-by-upregulation-of-endothelial-nitric-oxide-synthase-in-rho-associated-coiled-coil-containing-kinase-2-deficient-mice
#10
Yukio Hiroi, Kensuke Noma, Hyung-Hwan Kim, Nikola Sladojevic, Corey E Tabit, Yuxin Li, Guray Soydan, Salvatore Salomone, Michael A Moskowitz, James K Liao
BACKGROUND: Rho-associated kinases (ROCK1 and ROCK2) are important regulators of the actin cytoskeleton and endothelial nitric oxide synthase (eNOS). Because the phosphorylation of eukaryotic elongation factor-1A1 (eEF1A1) by ROCK2 is critical for eNOS expression, we hypothesized that this molecular pathway may play a critical role in neuroprotection following focal cerebral ischemia.Methods and Results:Adult male wild-type (WT) and mutant ROCK2 and eNOS-/- mice were subjected to middle cerebral artery occlusion (MCAO), and cerebral infarct size, neurological deficit and absolute cerebral blood flow were measured...
March 23, 2018: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/29337194/fasudil-ameliorates-the-ischemia-reperfusion-oxidative-injury-in-rat-hearts-through-suppression-of-myosin-regulatory-light-chain-nadph-oxidase-2-pathway
#11
Yi-Shuai Zhang, Li-Jing Tang, Hua Tu, Shi-Jing Wang, Bin Liu, Xiao-Jie Zhang, Nian-Sheng Li, Xiu-Ju Luo, Jun Peng
Fasudil is a potent Rho-kinase (ROCK) inhibitor and can relax smooth muscle or cardiac muscle contraction through decreasing the phosphorylation level of myosin regulatory light chain (p-MLC20 or p-MLC2v), while p-MLC2v can function as a transcription factor to promote the NADPH oxidase 2 (NOX2) expression in rat hearts subjected to ischemia/reperfusion (I/R). This study aims to explore whether fasudil can protect the rat hearts against I/R oxidative injury through suppressing NOX2 expression via reduction of p-MLC2v level...
March 5, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29336470/tnf-%C3%AE-induces-drp1-mediated-mitochondrial-fragmentation-during-inflammatory-cardiomyocyte-injury
#12
Yue-Liang Shen, Ying-Zhou Shi, Gai-Ge Chen, Lin-Lin Wang, Ming-Zhi Zheng, Hong-Feng Jin, Ying-Ying Chen
Dynamin-related peptide 1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes...
April 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29323739/fasudil-alleviates-pressure-overload-induced-heart-failure-by-activating-nrf2-mediated-antioxidant-responses
#13
Peng Guan, Yingran Liang, Na Wang
The RhoA/Rho-kinase cascade plays an important role in many aspects of cardiovascular function. This study aims to investigate the protective effects of fasudil, a Rho-kinase inhibitor, on pressure overload induced heart failure in rats. Pressure overload induced heart failure was induced in SD rats by banding the abdominal aorta for 8 weeks. The rats were divided into four groups: Sham, TAC, TAC plus low dose of fasudil and TAC plus high dose of fasudil group. Low dose and high dose fasudil were 5 mg/kg/day and 10 mg/kg/day respectively...
January 11, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29319354/inhibition-of-the-rhoa-rho-associated-coiled-coil-containing-protein-kinase-1-pathway-is-involved-in-the-therapeutic-effects-of-simvastatin-on-pulmonary-arterial-hypertension
#14
Wei-Hua Liu, Xiao-Hong Xu, Qin Luo, Hong-Liang Zhang, Yong Wang, Qun-Ying Xi, Zhi-Hui Zhao, Zhi-Hong Liu
BACKGROUND: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. METHODS: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i...
2018: Clinical and Experimental Hypertension: CHE
https://www.readbyqxmd.com/read/29189096/regulation-and-functions-of-rhou-and-rhov
#15
Richard G Hodge, Anne J Ridley
Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N- and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them...
November 30, 2017: Small GTPases
https://www.readbyqxmd.com/read/29136112/local-production-of-tenascin-c-acts-as-a-trigger-for-monocyte-macrophage-recruitment-that-provokes-cardiac-dysfunction
#16
Dounia Abbadi, Fanny Laroumanie, Mathilde Bizou, Joffrey Pozzo, Danièle Daviaud, Christine Delage, Denis Calise, Fréderique Gaits-Iacovoni, Marianne Dutaur, Florence Tortosa, Edith Renaud-Gabardos, Victorine Douin-Echinard, Anne-Catherine Prats, Jerome Roncalli, Angelo Parini, Nathalie Pizzinat
Aims: Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results: We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells...
January 1, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29066090/genetic-variants-associated-with-susceptibility-to-idiopathic-pulmonary-fibrosis-in-people-of-european-ancestry-a-genome-wide-association-study
#17
Richard J Allen, Joanne Porte, Rebecca Braybrooke, Carlos Flores, Tasha E Fingerlin, Justin M Oldham, Beatriz Guillen-Guio, Shwu-Fan Ma, Tsukasa Okamoto, Alison E John, Ma'en Obeidat, Ivana V Yang, Amanda Henry, Richard B Hubbard, Vidya Navaratnam, Gauri Saini, Norma Thompson, Helen L Booth, Simon P Hart, Mike R Hill, Nik Hirani, Toby M Maher, Robin J McAnulty, Ann B Millar, Philip L Molyneaux, Helen Parfrey, Doris M Rassl, Moira K B Whyte, William A Fahy, Richard P Marshall, Eunice Oballa, Yohan Bossé, David C Nickle, Don D Sin, Wim Timens, Nick Shrine, Ian Sayers, Ian P Hall, Imre Noth, David A Schwartz, Martin D Tobin, Louise V Wain, R Gisli Jenkins
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. METHODS: We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2)...
November 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/29061365/rho-specific-guanine-nucleotide-exchange-factors-rho-gefs-inhibition-affects-macrophage-phenotype-and-disrupts-golgi-complex
#18
Wei Chen, Yue Zhao, Xian C Li, Jacek Z Kubiak, Rafik M Ghobrial, Malgorzata Kloc
Macrophages play crucial role in tissue homeostasis and the innate and adaptive immune response. Depending on the state of activation macrophages acquire distinct phenotypes that depend on actin, which is regulated by small GTPase RhoA. The naive M0 macrophages are slightly elongated, pro-inflammatory M1 are round and M2 anti-inflammatory macrophages are elongated. We showed previously that interference with RhoA pathway (RhoA deletion or RhoA/ROCK kinase inhibition) disrupted actin, produced extremely elongated (hummingbird) macrophage phenotype and inhibited macrophage movement toward transplanted hearts...
December 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29045568/loss-of-protein-kinase-novel-1-pkn1-is-associated-with-mild-systolic-and-diastolic-contractile-dysfunction-increased-phospholamban-thr17-phosphorylation-and-exacerbated-ischaemia-reperfusion-injury
#19
Asvi A Francois, Kofo Obasanjo-Blackshire, James E Clark, Andrii Boguslavskyi, Mark R Holt, Peter J Parker, Michael S Marber, Richard J Heads
Aims: PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection. Methods and results: Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischaemia and reperfusion (I/R). Myocardial infarct size was doubled in PKN1 KO hearts compared to WT hearts. PKN1 was basally phosphorylated on the activation loop Thr778 PDK1 target site which was unchanged during I/R...
January 1, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29029794/rho-kinase-inhibition-reverses-impaired-ca-2-handling-and-associated-left-ventricular-dysfunction-in-pressure-overload-induced-cardiac-hypertrophy
#20
Yusuf Olgar, Murat Cenk Celen, Bilge Eren Yamasan, Nihal Ozturk, Belma Turan, Semir Ozdemir
Recent studies have implicated a relationship between RhoA/ROCK activity and defective Ca(2+) homeostasis in hypertrophic hearts. This study investigated molecular mechanism underlying ROCK inhibition-mediated cardioprotection against pressure overload-induced cardiac hypertrophy, with a focus on Ca(2+) homeostasis. Cardiac hypertrophy model was established by performing transverse aortic constriction (TAC) in 8-week-old male rats. Groups were assigned as SHAM, TAC and TAC+Fas (rats undergoing TAC and treated with fasudil)...
November 2017: Cell Calcium
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