Wars2 is a determinant of angiogenesis.

Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases

Titin-truncating variants affect heart function in disease cohorts and the general population

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease

Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade In Vitro and In Vivo

10.1158/1940-6207.CAPR-11-0420Cancer Prevention Research54631-64

<i>In vitro</i> experiments of treating metastatic HCC cells with Lic5.

<p>Treatment of HCC cells with Lic5 inactivated CDH17/β-catenin signaling pathway and induced apoptosis. (A) MHCC97L cells with high level of CDH17 were treated with an increasing concentration of Lic5 from 25 to 200 µg/mL. A dose-dependent reduction in the protein level of CDH17 was detected using western blot. (B) Confocal microscopy images showed a reduction in cellular levels of total and phospho-β-catenin (at Thr41 and Ser45) proteins after Lic5 treatment in MHCC97H cells. PBS was used as a negative control. Scale bar, 20 µm. (C) Real-time qPCR showed a time-dependent reduction of cyclin D1 gene expression level in MHCC97H cells after treatment with Lic5 for 18, 36 and 48 hours.*, <i>p</i> = 0.001493; **, <i>p</i> = 0.00001424; ***, <i>p</i> = 0.00001377, when compared to the Mock (PBS) or IgG control. Shown are the representative set of data of three independent experiments, with each column represents the mean values of triplicate data. All <i>p</i>-values were calculated using ANOVA test of GraphPad PRISM. (D) Western blots showed treatment with Lic5 induced cleavage of caspase-8 and -9, but not by the Mock and IgG controls.</p

Lic5 treatment inactivated Wnt/β-catenin signaling in HCC tumors.

<p>Mice having MHCC97L-derived tumors were subjected to single or combined treatment of Lic5 and cisplatin as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0072386#pone-0072386-g002" target="_blank">Fig. 2</a>. (A) Changes in the protein level of Wnt/β-catenin pathway components like β-catenin, cyclin D1 and retinoblastoma (Rb) in resected HCC tumors were detected using western blot. Suppression of CDH17 level using Lic5 accompanied with an inactivation of Wnt/β-catenin pathway, leading to reduction in the levels of β-catenin and cyclin D1 and induction in the level of Rb. β-Actin was used as a loading control. (B) Similar trend in the changes of the levels of β-catenin, cyclin D1 and Rb was observed in tissue sections of the HCC tumor xenografts using immunohistochemistry. Original magnification, ×400; scale bar, 80 µm.</p

Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways

10.1007/s00424-007-0321-4Pflugers Archiv European Journal of Physiology4554607-61

IL-11 is a crucial determinant of cardiovascular fibrosis

Fibrosis is a common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor4,5, but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases

IL-11 is a crucial determinant of cardiovascular fibrosis

Fibrosis is a common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor4,5, but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases