BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways

Qu, Xiuxia; Liu, Ying; Cao, Dayan; Chen, L. Jinghai; Liu, Zhuo; Ji, Hongrui; Chen, Yu‐Wen; Zhang, Wenjun; Zhu, Ping; Xiao, Deyong; Li, Xiaohui; Shou, Weinian; Chen, Hanying

doi:10.1074/jbc.ra119.010943

Cited by 29 publications

(24 citation statements)

References 41 publications

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“…A subsequent binding of SMAD1/5/8 and co-SMAD (SMAD4) and activation of NKX2.5 , the determinant of cardiac development and the common-enhanced gene in our case, through both SMAD complex and GATA-4 ( Brown et al, 2004 ) might be a key determination step of cardiogenesis in atrial appendage. The role of BMP10 in the adult heart remains elusive, but as reported recently BMP10 may play multifunctional roles not only in promoting cardiac development in prenatal stages but also in inhibiting cardiomyocyte apoptosis and cardiac fibrosis in adults ( Qu et al, 2019 ). In the downstream of this canonical pathway, cardiac transcription factors were predicted to activate target genes including AA-specific and LV-enhanced genes: natriuretic peptide B ( NPPB ) and natriuretic peptide A ( NPPA ).…”

Section: Resultsmentioning

confidence: 99%

Integrative Analysis Revealing Human Heart-Specific Genes and Consolidating Heart-Related Phenotypes

Ahn

Lee

2020

Front. Genet.

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Elucidating expression patterns of heart-specific genes is crucial for understanding developmental, physiological, and pathological processes of the heart. The aim of the present study is to identify functionally and pathologically important heart-specific genes by performing the Ingenuity Pathway Analysis (IPA). Through a median-based analysis of tissue-specific gene expression based on the Genotype-Tissue Expression (GTEx) data, we identified 56 genes with heart-specific or elevated expressions in the heart (heart-specific/enhanced), among which three common heart-specific/enhanced genes and four atrial appendage-specific/enhanced genes were unreported regarding the heart. Differential expression analysis further revealed 225 differentially expressed genes (DEGs) between atrial appendage and left ventricle. Our integrative analyses of those heart-specific/enhanced genes and DEGs with IPA revealed enriched heart-related traits and diseases, consolidating evidence of relationships between these genes and heart function. Our reports on comprehensive identification of heart-specific/enhanced genes and DEGs and their relation to pathways associated with heart-related traits and diseases provided molecular insights into essential regulators of cardiac physiology and pathophysiology and potential new therapeutic targets for heart diseases.

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Section: Resultsmentioning

confidence: 99%

Integrative Analysis Revealing Human Heart-Specific Genes and Consolidating Heart-Related Phenotypes

Ahn

Lee

2020

Front. Genet.

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“…Bmp10 –/– embryos were found to succumb to HF induced by severely hypoplastic hearts [ 19 ] and transgenic mice with overexpression of Bmp10 exhibited a 50% reduction in heart size [ 33 ]. In addition, Bmp10 overexpression has been reported to exert a cardioprotective effect in ISO-induced HF models [ 34 ]. In our study, we found that cardiac-specific Gsα deletion downregulated Bmp10-mediated signaling and consequently provoked cardiac remodeling and found that rhBMP10 might ameliorate the phenotype induced by cardiac-specific Gsα deletion.…”

Section: Discussionmentioning

confidence: 99%

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Yin

Zhao

et al. 2021

Cell Death Discov.

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The stimulatory G-protein alpha subunit (Gsα), a ubiquitously expressed protein, mediates G-protein receptor-stimulated signal transduction. To investigate the functions of Gsα in cardiomyocytes. We developed transverse aortic constriction (TAC)-induced heart failure mouse models and tamoxifen-inducible transgenic mice with cardiac-specific Gsα disruption. We detected alterations in Gsα expression in TAC-induced heart failure mice. Moreover, we examined cardiac function and structure in mice with genetic Gsα deletion and investigated the underlying molecular mechanisms of Gsα function. We found that Gsα expression increased during the compensated cardiac hypertrophy period and decreased during the heart failure period. Moreover, cardiac-specific Gsα disruption deteriorated cardiac function and induced severe cardiac remodeling. Mechanistically, Gsα disruption decreased CREB1 expression and inhibited the Bmp10-mediated signaling pathway. In addition, we found that Gsα regulates Bmp10 expression through the binding of CREB1 to the Bmp10 promoter. Our results suggest that fluctuations in Gsα levels may play a vital role in the development of heart failure and that loss of Gsα function facilitates cardiac remodeling.

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“…Follow-up analysis revealed that 116 of these genes were differentially expressed in tumour hosts receiving ACVR2B/Fc compared with the untreated tumour bearers. Among these, Bmp10, which has shown to induce cardiomyocyte proliferation, preserve cardiac function following myocardial infarction, and prevent cardiomyocyte death and development of cardiac fibrosis following insult, 81,82 was down-regulated 30-fold in tumour hosts, whereas ACVR2B/ Fc increased Bmp10 five-fold in tumour hosts. Similarly, GLP1R was reduced 51-fold in the tumour-bearing mice and increased 71-fold in ACVR2B/Fc-treated HCT116 hosts.…”

Section: Discussionmentioning

confidence: 99%

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

Huot

Narasimhan

et al. 2020

J cachexia sarcopenia muscle

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Background Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. Methods NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. Results mHCT116 hosts displayed losses in fat mass (À 79%, P < 0.0001), bone mass (À 39%, P < 0.05), and SKM mass (quadriceps: À 22%, P < 0.001), in line with reduced muscle cross-sectional area (À 24%, P < 0.01) and plantarflexion force (À 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: À 16%, P < 0.0001; fractional shortening %: À 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass (+ 238%, P < 0.001), bone mass (+ 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force (+ 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Conclusions Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.

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BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways

Cited by 29 publications

References 41 publications

Integrative Analysis Revealing Human Heart-Specific Genes and Consolidating Heart-Related Phenotypes

Integrative Analysis Revealing Human Heart-Specific Genes and Consolidating Heart-Related Phenotypes

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

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