Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains

Gomes, Aldrin V.; Kazmierczak, Katarzyna; Cheah, Jenice X.; Gilda, Jennifer E.; Yuan, Chen; Zhou, Zhiqun; Szczesna‐Cordary, Danuta

doi:10.1007/s10974-015-9434-0

Cited by 9 publications

(8 citation statements)

References 71 publications

(101 reference statements)

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“…Proteins that contained similar peptides and could not be differentiated based on MS/MS analysis alone were grouped to satisfy the principles of parsimony. Proteins sharing significant peptide evidence were grouped into clusters 20 . Channels were corrected as described in the supplementary text 21 .…”

Section: Lc-ms/ms Using 10-plex Tmt Proteomics Sample Preparation Pmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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Ibuprofen, an inhibitor of prostanoid biosynthesis, is a common pharmacological agent used for the management of pain, inflammation and fever. However, the chronic use of ibuprofen at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on liver remain unclear. To determine the mechanisms and signaling pathways affected by ibuprofen (100 mg/kg/day for seven days), we performed proteomic profiling of male mice liver with quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) using ten-plex tandem mass tag (TMT) labeling. More than 300 proteins were significantly altered between the control and ibuprofen-treated groups. The data suggests that several major pathways including (1) energy metabolism, (2) protein degradation, (3) fatty acid metabolism and (4) antioxidant system are altered in livers from ibuprofen treated mice. Independent validation of protein changes in energy metabolism and the antioxidant system was carried out by Western blotting and showed sex-related differences. Proteasome and immunoproteasome activity/expression assays showed ibuprofen induced gender-specific proteasome and immunoproteasome dysfunction in liver. The study observed multifactorial gender-specific ibuprofen-mediated effects on mice liver and suggests that males and females are affected differently by ibuprofen. Ibuprofen, a propionic acid derivative, is the most common over-the-counter nonsteroidal anti-inflammatory (NSAID) drug used to treat fever, pain, inflammation and many other disorders 1. It has been included as a major medicine in the Essential Drugs List of the World Health Organization 2. Ibuprofen at low over-the-counter doses (800-1200 mg/day) is used to treat muscular aches, backaches, toothaches, and fever. At higher doses (1800-2400 mg/day), ibuprofen is prescribed for the treatment of chronic conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis 3. Ibuprofen is a non-selective inhibitor of the cyclo-oxygenase (COX) isozymes COX-1 and COX-2 that converts arachidonic acid into prostaglandins including thromboxane and prostacyclin 1. The anti-inflammatory, antipyretic and analgesic effects of ibuprofen are mediated through the inhibition of prostaglandins E2 (PGE2) and I2 (PGI2) production by blocking COX activity 1. Both PGE2 and PGI2 are pro-inflammatory prostanoids that increase vascular permeability, promote leukocyte infiltration and increase edema formation 4. The clearance of ibuprofen is mediated through oxidative metabolism by multiple cytochrome P450 (CYP) enzymes (CYP2C9, CYP2C8) to inactive primary metabolites including 3-hydroxy-ibuprofen, carboxy ibuprofen and 2-hydroxy-ibuprofen 5,6. Most of the ibuprofen is metabolized in liver, while only a small percentage of unchanged drug is excreted in the urine 5. The liver plays a key role in energy metabolism and is essential for whole body homeostasis via the regulation of glucose, lipid, and amino acid ...

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Section: Lc-ms/ms Using 10-plex Tmt Proteomics Sample Preparation Pmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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“…Hearts and SOL muscles from three 8-mo-old male R58Q, and three 7-mo-old male WT mice were collected for proteomic studies. Protein isolation, sample processing, and data analysis were performed as previously described (20,32). Statistically significant changes in protein expression in the hearts (Supplemental Table S1) or SOL muscles ( Supplemental Table S2) of R58Q vs. WT mice are shown with the positive fold change (FC) values indicating the up-regulated proteins and the negative FC indicating the proteins that were down-regulated in the mutant mouse model.…”

Section: Proteomics Experimentsmentioning

confidence: 99%

“…The comparison between 3 heart and SOL WT and 3 heart and SOL R58Q samples was conducted by using TMT 6-plex, which allows the direct comparison between 6 different samples in the same liquid chromatography tandem mass spectrometry analysis. Each set of TMT labeling was performed as previously described (20,32). Briefly, TMTlabeled peptides were fractionated by using ion exchange columns (SCX SpinTips; Protea Biosciences, Morgantown, WV, USA).…”

Section: Proteomics Experimentsmentioning

confidence: 99%

“…Each eluted fraction was desalted by using SDB columns (GL Sciences, Tokyo, Japan), dried using a speed vacuum, and suspended in 5% acetonitrile, 0.1% TFA. Each desalted fraction was then analyzed by liquid chromatography tandem mass spectrometry on a Thermo Scientific Q ExactivePlus Orbitrap Mass Spectrometer with an attached Proxeon Nanospray source and a Waters UPLC (Waters, Milford, MA, USA) as previously described (20,32). Scaffold Q+ (v.4.4.1; Proteome Software, Portland, OR, USA) was used to quantitate labeling-based quantitation (TMT) peptide and protein identifications.…”

Section: Proteomics Experimentsmentioning

confidence: 99%

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Slow‐twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain

et al. 2018

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Myosin light chain 2 (MYL2) gene encodes the myosin regulatory light chain (RLC) simultaneously in heart ventricles and in slow‐twitch skeletal muscle. Using transgenic mice with cardiac‐specific expression of the human R58Q‐RLC mutant, we sought to determine whether the hypertrophic cardiomyopathy phenotype observed in papillary muscles (PMs) of R58Q mice is also manifested in slow‐twitch soleus (SOL) muscles. Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force that was not observed in the fast‐twitch extensor digitorum longus muscles of R58Q vs. wild‐type‐RLC mice, but mutant animals did not display gross muscle weakness in vivo. Consistent with SOL muscle abnormalities in R58Q vs. wild‐type mice, myosin ATPase staining revealed a decreased proportion of fiber type I/type II only in SOL muscles but not in the extensor digitorum longus muscles. The similarities between SOL muscles and PMs of R58Q mice were further supported by quantitative proteomics. Differential regulation of proteins involved in energy metabolism, cell‐cell interactions, and protein‐protein signaling was concurrently observed in the hearts and SOL muscles of R58Q mice. In summary, even though R58Q expression was restricted to the heart of mice, functional similarities were clearly observed between the hearts and slow‐twitch skeletal muscle, suggesting that MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC.—Kazmierczak, K., Liang, J., Yuan, C.‐C, Yadav, S., Sitbon, Y. H., Walz, K., Ma, W., Irving, T. C., Cheah, J. X., Gomes, A. V., Szczesna‐Cordary, D. Slow‐twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain. FASEB J. 33, 3152–3166 (2019). http://www.fasebj.org

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“…In addition, Tg-A57G animals showed a significant upregulation of hypertrophic markers (ANP, BNP, collagen VIIIa) that were activated upon exercise, along with a visible increase in heart size and occurrences of fibrosis, especially in the interventricular septum 60 . Proteomic analysis of Tg-A57G hearts demonstrated alterations in Ca 2+ homeostasis along with fatty acid metabolism, suggesting these may be important in the pathological cardiac remodeling observed in Tg-A57G myocardium 33 .…”

Section: Glu56gly (E56g)mentioning

confidence: 96%

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

Yadav

Sitbon

Kazmierczak

et al. 2019

Pflugers Arch - Eur J Physiol

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Genetic cardiomyopathies, a group of cardiovascular disorders based on ventricular morphology and function, are amongst the leading causes of morbidity and mortality worldwide. Such genetically-driven forms of hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathies are chronic, debilitating diseases that result from biomechanical defects in cardiac muscle contraction and frequently progress to heart failure (HF). Locus and allelic heterogeneity, as well as clinical variability combined with genetic and phenotypic overlap between different cardiomyopathies, have challenged proper clinical prognosis and provided an incentive for identification of pathogenic variants. This review attempts to provide an overview of inherited cardiomyopathies with a focus on their genetic etiology in myosin regulatory (RLC) and essential (ELC) light chains, which are EF-hand protein family members with important structural and regulatory roles. From the clinical discovery of cardiomyopathy-linked light chain mutations in patients to an array of exploratory studies in animals, reconstituted, and recombinant systems, we have summarized the current state of knowledge on light chain mutations and how they induce physiological disease states via biochemical and biomechanical alterations at the molecular, tissue and organ level. Cardiac myosin RLC phosphorylation and the N-terminus ELC have been discussed as two important emerging modalities with important implications in the regulation of myosin motor function and thus cardiac performance. A comprehensive understanding of such triggers is absolutely necessary for the development of target-specific rescue strategies to ameliorate or reverse the effects of myosin light chain-related inherited cardiomyopathies.

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Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains

Cited by 9 publications

References 71 publications

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Slow‐twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain

Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains

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