Calponin1 inhibits dilated cardiomyopathy development in mice through the εPKC pathway

Lu, Dongfang; Zhang, Li; Bao, Dan; Lu, Yingdong; Zhou, Xu; Liu, Ning; Ge, Wenping; Gao, Xiang; Li, Hongliang; Zhang, Lianfeng

doi:10.1016/j.ijcard.2014.02.032

Cited by 20 publications

(21 citation statements)

References 55 publications

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“…6A). We also observed modest decreases in the troponin/tropomyosin complex and a large increase in atrial isoforms of regulatory and essential myosin light chains, which have been associated with heart disease (34), as well as increased levels of calponins, proteins that interact with actin and tropomyosin, which, when overexpressed, can partially rescue hearts from dilated cardiomyopathy (35). A survey of the glycolytic and glucose oxidation pathways showed no changes in core pathway enzymes ( Fig.…”

Section: Resultsmentioning

confidence: 63%

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Bround¹,

Wambolt

Cen³

et al. 2016

Journal of Biological Chemistry

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Cardiac ryanodine receptor (Ryr2) Ca release channels and cellular metabolism are both disrupted in heart disease. Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arrhythmia, and reduced heart rate. Acute total Ryr2 ablation also impaired metabolism, but it was not clear whether this was a cause or consequence of heart failure. Previous in vitro studies revealed that Ca flux into the mitochondria helps pace oxidative metabolism, but there is limited in vivo evidence supporting this concept. Here, we studied heart-specific, inducible Ryr2 haploinsufficient (cRyr2Δ50) mice with a stable 50% reduction in Ryr2 protein. This manipulation decreased the amplitude and frequency of cytosolic and mitochondrial Ca signals in isolated cardiomyocytes, without changes in cardiomyocyte contraction. Remarkably, in the context of well preserved contractile function in perfused hearts, we observed decreased glucose oxidation, but not fat oxidation, with increased glycolysis. cRyr2Δ50 hearts exhibited hyperphosphorylation and inhibition of pyruvate dehydrogenase, the key Ca-sensitive gatekeeper to glucose oxidation. Metabolomic, proteomic, and transcriptomic analyses revealed additional functional networks associated with altered metabolism in this model. These results demonstrate that Ryr2 controls mitochondrial Ca dynamics and plays a specific, critical role in promoting glucose oxidation in cardiomyocytes. Our findings indicate that partial RYR2 loss is sufficient to cause metabolic abnormalities seen in heart disease.

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Section: Resultsmentioning

confidence: 63%

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Bround¹,

Wambolt

Cen³

et al. 2016

Journal of Biological Chemistry

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“…MYH6 is a famous cardiac muscle myosin gene and mutations of this gene are implicated in cardiomyopathy in various studies [ 18 ]. Inhibition of CNN1 expression may disrupt its suppression of cardiomyopathy through the εPKC pathway [ 19 ]. In addition, both SRF and MEF2C may regulate the expression of NPPA , which was overexpressed in patients in our results.…”

Section: Discussionmentioning

confidence: 99%

Construction of microRNA and transcription factor regulatory network based on gene expression data in cardiomyopathy

Wang

Xing

et al. 2014

Eur J Med Res

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BackgroundCardiomyopathy is a progressive myocardial disorder. Here, we attempted to reveal the possible mechanism of cardiomyopathy at the transcription level with the roles of microRNAs (miRNAs) and transcription factors (TFs) taken into account.MethodWe firstly identified differentially expressed genes (DEGs) between cardiomyopathy patients and controls with data from the gene expression omnibus (GEO) database. DEGs were associated with the canonical pathways, molecular and cellular functions, physiological system development and function in the Ingenuity Knowledge Base by using the Ingenuity Pathway Analysis (IPA) software. TFs and miRNAs that DEGs significantly enriched were identified and a double-factor regulatory network was constructed.ResultsA total of 1,680 DEGs were identified. The DEGs were enriched for various pathways, with glucocorticoid receptor signaling as the most significant. A double-factor regulatory network was constructed, including seven TFs and two miRNAs. A subnetwork under the regulation of MEF2C and SRF was also constructed to illustrate their regulatory effects on cardiac functions.ConclusionOur results may provide new understanding of cardiomyopathy and may facilitate further therapeutic studies.

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“…[25][26][27][28] cDNA encoding mouse Dkk3 (GenBank accession no. NM_015814) was cloned into an expression plasmid under the α-MHC promoter and the heart-specific Dkk3 transgenic mouse (referred as Dkk3-ov) was generated by microinjection.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…Echocardiography M-mode echocardiography was performed at 1, 3, 6, and 10 months of age on each mouse with the small animal echocardiography analysis system (Vevo770, Canada) as described previously. 27,28 Histological Analysis For light microscopy, cardiac tissue from mice at 6 months of age was fixed in 4% formaldehyde and mounted in paraffin blocks, and sections were stained with H&E or Masson trichrome as described previously. 27,28 Myocytes were analyzed by an observer blinded to the mouse genotypes.…”

Section: Survival Analysismentioning

confidence: 99%

“…27,28 After performing SDS-PAGE and transferring gels to nitrocellulose (Millipore), the membranes were incubated at 4°C overnight with antibodies against Dkk3 (R&D), β-catenin (Abcam), c-Myc (Abcam), Axin2 (Abcam), Dvl1 (Abcam), phospho-CaMKII (Thr286) (Cell Signaling), CaMKII (Cell Signaling), phospho-HDAC4 (Ser632) (Cell Signaling), HDAC4 (Cell Signaling), phospho-SAPK/JNK (Thr183/Tyr185) (Cell Signaling), SAPK/JNK (Cell Signaling), phospho-protein kinase Cα/β (PKCα/β) (Thr638/641) (Cell Signaling), PKCα (Cell Signaling), phospho-PKCδ (Thr505) (Cell Signaling), and PKCδ (Cell Signaling). After incubation with the appropriate secondary antibodies for 1 h at room temperature, antibody binding was detected with HRP-conjugated immunoglobulin G (Santa Cruz) using a chemiluminescence detection system (Santa Cruz).…”

Section: Protein Extraction and Immunoblottingmentioning

confidence: 99%

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Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

Bao

Dong

et al. 2016

Laboratory Investigation

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To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3 interferes with Wnt signaling in heart tissues remains unknown. Here, we demonstrate that strong Dkk3 expression was markedly downregulated in adult hearts from WT mice, and Dkk3 expression was upregulated suddenly in hearts from DCM mouse models. Using Dkk3 transgenic and knockout mice, as well as cTnT R141W transgenic mice, which manifests progressive chamber dilation and contractile dysfunction and has pathologic phenotypes similar to human DCM patients, we determined that transgenic expression of Dkk3 increased survival rate, improved cardiac morphology breakage and dysfunction, and ameliorated cardiac pathological changes in the cTnT R141W mice. In contrast, Dkk3 knockout reduced the survival rate and aggravated the pathological phenotypes of the cTnT R141W mice. The protective effects of Dkk3 appeared clearly at 3 months of age, peaked at 6 months of age, and decreased at 10 months of age in the cTnT R141W mice. Furthermore, we determined that Dkk3 upregulated Dvl1 (Dishevelled 1) and key proteins of the canonical Wnt pathway (cytoplasmic and nuclear β-catenin, c-Myc, and Axin2) and downregulated key proteins of the noncanonical Wnt pathway (c-Jun N-terminal kinase (JNK), Ca 2+ /calmodulin-dependent protein kinase II (CAMKII), and histone deacetylase 4 (HDAC4)). In contrast, Dkk3 knockout reversed these changes in the cTnT R141W mice. In summary, Dkk3 could prevent FDCM development in mice, especially in the compensatory stage, and probably through activation of the canonical and inhibition of the noncanonical Wnt pathway, which suggested that Dkk3 could serve as a therapeutic target for the treatment of cardiomyopathy and heart failure.

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Calponin1 inhibits dilated cardiomyopathy development in mice through the εPKC pathway

Cited by 20 publications

References 55 publications

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Construction of microRNA and transcription factor regulatory network based on gene expression data in cardiomyopathy

Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

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