TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
activation; cation channel trpv4; contraction; disease; fibroblasts; gene-expression; induced lung injury; mechanisms; pathogenesis; Research & Experimental Medicine; tgf-beta
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-beta; however, it is not clear how fibroblasts sense and transmit the mechanical signal(s) that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with IPF. Moreover, TRPV4-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction. TRPV4 channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. TRPV4 activity modulated TGF-beta 1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the alpha-SMA transcription coactivator (MRTF-A). Together, these data indicate that TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases.
Rahaman S O; Grove L M; Paruchuri S; Southern B D; Abraham S; Niese K A; Scheraga R G; Ghosh S; Thodeti C K; Zhang D X; Moran M M; Schilling W R; Tschumperlin D J; Olman M A
Journal of Clinical Investigation
2014
2014-12
Journal Article
<a href="http://doi.org/10.1172/jci75331" target="_blank" rel="noreferrer noopener">10.1172/jci75331</a>
Comparison of Sonography and Scintigraphy in the Evaluation of Gallbladder Functional Studies With Cholecystokinin
pain; Acoustics; ultrasonography; Radiology; disease; Nuclear Medicine & Medical Imaging; sonography; contraction; gallstones; cholecystokinin; cholescintigraphy; chronic acalculous cholecystitis; ejection fraction; gallbladder ejection fraction; infusion; scintigraphy
Objective. Both sonography and scintigraphy have been used to evaluate gallbladder function with the use of sincalide (cholecystokinin [CCK]). However, the reported ejection fractions (EFs) for the two modalities are not the same. The techniques measure slightly different parameters. This study directly compared both techniques performed simultaneously on the same participants. Methods. Twenty healthy volunteers were evaluated with sonography and scintigraphy to estimate the gallbladder EF simultaneously. The gallbladder EF was calculated at 5-minute intervals for 1 hour. Results. The mean El's +/- SD were 66.3% +/- 20% and 49% +/- 29% for sonography and scintigraphy, respectively. The mean times to the peak EF were 38 12 and 33 9 minutes for sonography and scintigraphy. An average time of 34 minutes was noted after radiopharmaceutical injection before CCK administration for the scintigraphic studies. The earliest time to the peak EF for sonography was 15 minutes, and the latest time to the peak EF was 60 minutes (mode, 40 minutes); for scintigraphy, the earliest and latest times were 15 and 50 minutes (mode, 30 minutes), respectively. One participant could not be evaluated secondary to nonfilling of the gallbladder on scintigraphy. There was wider variability of the gallbladder EF with scintigraphy than sonography. Conclusions. Scintigraphy estimated a lower EF than sonography, had wider EF variability than sonography, and required additional time (>30 minutes more) to complete the study. Scintigraphy could not be performed in 5% of the participants because of nonfilling of the gallbladder The use of sonography to estimate the gallbladder EF is less time-consuming and less costly. With these techniques, the range of normal gallbladder El's should be adjusted for the technique used.
Barr R G; Kido T; Grajo J R
Journal of Ultrasound in Medicine
2009
2009-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.7863/jum.2009.28.9.1143" target="_blank" rel="noreferrer noopener">10.7863/jum.2009.28.9.1143</a>
Interplay between obesity and aging on myocardial geometry and function: Role of leptin-STAT3-stress signaling
Background: Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function.
Methods: Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison.
Results: Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2- and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2- yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response.
Conclusions: Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress.
Wei Jin
Fei Tu
Feng Dong
Qinqin Deng
Miyesaier Abudureyimu
Wei Yu
Guo-Jun Cai
Jian-Ming Pei
Zhaohui Pei
Jun Ren
Biochim Biophys Acta Gen Subj
. 2023 Feb;1867(2):130281. doi: 10.1016/j.bbagen.2022.130281. Epub 2022 Nov 18.
2022
English