Defining the molecular signatures of human right heart failure

Williams, Jeremy C.; Cavus, Omer; Loccoh, Eméfah; Adelman, Sara; Daugherty, John C.; Smith, Sakima A.; Canan, Benjamin D.; Janssen, Paul M.L.; Koenig, Sara N.; Kline, Crystal F.; Mohler, Peter J.; Bradley, Elisa A.

doi:10.1016/j.lfs.2018.01.021

Cited by 22 publications

(20 citation statements)

References 64 publications

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“…Next, we found the functional enrichment of the hub genes associated with HF or ISCH or CMP were similar with those for the blue module. Williams and his colleagues found that SMOC2 was differentially expressed in failing right ventricular, and was potential targets for further study on HF [42]. A study revealed that SMOC2 could modulate fibroblast proliferation and extracellular matrix deposition [43].…”

Section: Discussionmentioning

confidence: 99%

Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure

et al. 2020

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Background: Left-sided heart failure (HF) is documented as a key prognostic factor in HF. However, the relative molecular mechanisms underlying left-sided HF is unknown. The purpose of this study is to unearth significant modules, pivotal genes and candidate regulatory components governing the progression of left-sided HF by bioinformatical analysis. Methods: A total of 319 samples in GSE57345 dataset were used for weighted gene correlation network analysis (WGCNA). ClusterProfiler package in R was used to conduct functional enrichment for genes uncovered from the modules of interest. Regulatory networks of genes were built using Cytoscape while Enrichr database was used for identification of transcription factors (TFs). The MCODE plugin was used for identifying hub genes in the modules of interest and their validation was performed based on GSE1869 dataset. Results: A total of six significant modules were identified. Notably, the blue module was confirmed as the most crucially associated with left-sided HF, ischemic heart disease (ISCH) and dilated cardiomyopathy (CMP). Functional enrichment conveyed that genes belonging to this module were mainly those driving the extracellular matrixassociated processes such as extracellular matrix structural constituent and collagen binding. A total of seven transcriptional factors, including Suppressor of Zeste 12 Protein Homolog (SUZ12) and nuclear factor erythroid 2 like 2 (NFE2L2), adrenergic receptor (AR), were identified as possible regulators of coexpression genes identified in the blue module. A total of three key genes (OGN, HTRA1 and MXRA5) were retained after validation of their prognostic value in left-sided HF. The results of functional enrichment confirmed that these key genes were primarily involved in response to transforming growth factor beta and extracellular matrix.

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Section: Discussionmentioning

confidence: 99%

Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure

et al. 2020

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“…Above all, our study stands out for its unbiased, comprehensive approach to identifying molecular pathophysiological signaling specific to the failing RV. Prior transcriptomic analyses of animal models and human tissue have relied on differential-expression and pathway analyses without subsequent experimental and mechanistic validation studies of proposed molecular signatures of RVF (13)(14)(15)(16)(17)(18)(19)(20). Although single-gene and differential-expression analyses are powerful tools, there are a number of advantages with WGCNA (59).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have been challenged by limitations of commonly used animal models that were developed to study pulmonary vascular disease rather than RV dysfunction or biventricular HF. Some studies have sought to identify molecular signatures of RVF, using animal models (13)(14)(15)(16)(17) or human tissue (18)(19)(20). Most of these were limited to animal models or patients with RV dysfunction but not RVF (13,14,16,18,19).…”

Section: Introductionmentioning

confidence: 99%

“…Most of these were limited to animal models or patients with RV dysfunction but not RVF (13,14,16,18,19). These prior studies did not pursue experimental validation or mechanistic studies of their potential molecular signatures of RV dysfunction (13)(14)(15)(16)(17)(18)(19)(20). All relied on biased pathway analyses of select differentially expressed genes.…”

Section: Introductionmentioning

confidence: 99%

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WIPI1 is a conserved mediator of right ventricular failure

Tzimas¹,

Rau²,

Buergisser³

et al. 2019

JCI Insight

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“…Both intramembranous and alveolar bone repair also require de novo coupling with angiogenesis 38 wherein SMOC2 functions in vascular patterning may be augmented during injury-induced revascularization 14 . SMOC2 is differentially increased in failing human heart, potentially marking injury-induced myocardial ischemia and/or fibrosis 39 . Smoc2 mutants could serve as a novel model to understand tissue repair, particularly in non-invasive therapy as anti-inflammatory (ibuprofen) treatment was shown to normalize defects in our experimental system.…”

Section: Smoc2 Is Required For Bone Repair and During Periodontal Agingmentioning

confidence: 99%

Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

Morkmued¹,

Clauss²,

Schuhbaur³

et al. 2020

Sci Rep

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Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components (Odontogenic ameloblast-associated protein) and dentin dysplasia targets (Dentin matrix acidic phosphoprotein 1). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2−/− mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2−/− mutants, reducing matrix metalloprotease (Mmp)9. Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.

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Defining the molecular signatures of human right heart failure

Cited by 22 publications

References 64 publications

Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure

Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure

WIPI1 is a conserved mediator of right ventricular failure

Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

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