Reduced hybrid/complex N-glycosylation disrupts cardiac electrical signaling and calcium handling in a model of dilated cardiomyopathy

Huang

BioMed Research International

et al. 2021

Objective. Multiple genes have been identified to cause dilated cardiomyopathy (DCM). Nevertheless, there is still a lack of comprehensive elucidation of the molecular characteristics for DCM. Herein, we aimed to uncover putative molecular features for DCM by multiomics analysis. Methods. Differentially expressed genes (DEGs) were obtained from different RNA sequencing (RNA-seq) datasets of left ventricle samples from healthy donors and DCM patients. Furthermore, protein-protein interaction (PPI) analysis was then presented. Differentially methylated genes (DMGs) were identified between DCM and control samples. Following integration of DEGs and DMGs, differentially expressed and methylated genes were acquired and their biological functions were analyzed by the clusterProfiler package. Whole exome sequencing of blood samples from 69 DCM patients was constructed in our cohort, which was analyzed the maftools package. The expression of key mutated genes was verified by three independent datasets. Results. 1407 common DEGs were identified for DCM after integration of the two RNA-seq datasets. A PPI network was constructed, composed of 171 up- and 136 downregulated genes. Four hub genes were identified for DCM, including C3 ( degree = 24 ), GNB3 ( degree = 23 ), QSOX1 ( degree = 21 ), and APOB ( degree = 17 ). Moreover, 285 hyper- and 321 hypomethylated genes were screened for DCM. After integration, 20 differentially expressed and methylated genes were identified, which were associated with cell differentiation and protein digestion and absorption. Among single-nucleotide variant (SNV), C>T was the most frequent mutation classification for DCM. MUC4 was the most frequent mutation gene which occupied 71% across 69 samples, followed by PHLDA1, AHNAK2, and MAML3. These mutated genes were confirmed to be differentially expressed between DCM and control samples. Conclusion. Our findings comprehensively analyzed molecular characteristics from the transcriptome, epigenome, and genome perspectives for DCM, which could provide practical implications for DCM.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

[Retracted] Multiomics Analysis of Transcriptome, Epigenome, and Genome Uncovers Putative Mechanisms for Dilated Cardiomyopathy

Huang

BioMed Research International

et al. 2021

“…Protein glycosylation is a posttranslational modification essential for protein functions such as proper folding, targeting to cellular compartments, and modulating receptor/ion channel activities ( Ohtsubo and Marth, 2006 ; Ednie et al, 2019 ). The oligosaccharides of cell surface glycoproteins can regulate recognition processes, such as signal transduction, cell adhesion, immune response, and host–pathogen interactions.…”

Section: Discussionmentioning

confidence: 99%

Stachytine Hydrochloride Improves Cardiac Function in Mice with ISO-Induced Heart Failure by Inhibiting the α-1,6-Fucosylation on N-Glycosylation of β1AR

Guo

Yang

et al. 2022

Front. Pharmacol.

Background: Cardiovascular diseases have become a major public health problem that seriously threatens human health. The cumulative effects of various cardiovascular events will eventually develop into chronic heart insufficiency and even heart failure, and the β1 adrenergic receptor signal pathway plays an important role in this process. Stachytine hydrochloride is the main active ingredient of Yimucao, which is a traditional Chinese medicine used to treat gynecological diseases. Modern studies have found that stachytine hydrochloride has a good cardioprotective effect, but it is still unclear whether stachytine hydrochloride has an effect on the β1 adrenergic receptor signal pathway. The purpose of this study is to explore the effect of stachytine hydrochloride on the β1 adrenergic receptor signal pathway.Method: In this study, a continuous infusion of isoproterenol (40 mg/kg/day) was administered to mice and ventricular myocytes explored the potential mechanism of stachytine hydrochloride (12 mg/kg/day) on the β1 adrenergic receptor signal pathway in the heart. Evaluate changes in cardiac morphology and function by echocardiography, cardiac hemodynamics, and histological methods, and detect molecular changes by Western blot and immunofluorescence. Treat primary cultured adult mouse or neonatal rat ventricular myocytes with or without isoproterenol (0.1 μMol), PNGase F (10–2 units/ml), and stachytine hydrochloride (10 μMol) at different time points. Detect α-1,6-fucosylation on N-glycosylation, calcium transient, contraction, and relaxation function and related signals.Results: Stachytine hydrochloride reduces cardiac remodeling and modulates hemodynamic parameters during chronic β1 adrenergic receptor activation in vivo. The N-glycosylation of β1 adrenergic receptors decreased after continuous isoproterenol stimulation, while stachytine hydrochloride can increase the N-glycosylation of β1AR in the heart of mice with isoproterenol-induced heart failure. Decreased N-glycosylation of β1 adrenergic receptors will downregulate the cAMP/PKA signal pathway and inhibit myocardial excitation and contraction coupling. Stachytine hydrochloride significantly reduced isoproterenol-induced cardiac N-linked glycoproteins with α-1,6-fucosylation.Conclusion: Our results show that stachytine hydrochloride inhibits the synthesis of α-1,6-fucosylation on the N-terminal sugar chain by reducing α-1,6-fucosyltransferase (FUT8) and α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A (MGAT4a), upregulating the N-glycosylation level on β1 adrenergic receptors, and maintaining cAMP/PKA signal pathway activation.

“…Another example where N -glycosylation is involved in cardiomyocyte function is the subunit α2δ1 of the Ca2+ channel, which is needed to maintain the basic cellular electrophysiological properties and control cardiac contractility. This function seems to be regulated by hybrid/complex N -glycosylation, and reduction of this process is sufficient to lead to dilated cardiomyopathy and early death in mice with depleted mannosyl (α-1,3-)-glycoprotein β-1,2- N -acetylglucosaminyl transferase ( Ednie et al, 2019a ; Ednie et al, 2019b ).…”

Section: N- Glycosylation Regulates Crucial Functions In Cardiomyocytesmentioning

confidence: 99%

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease

Loaeza-Reyes

Zenteno

Moreno-Rodríguez

et al. 2021

Front. Mol. Biosci.

The cardiovascular system is a complex and well-organized system in which glycosylation plays a vital role. The heart and vascular wall cells are constituted by an array of specific receptors; most of them are N- glycosylated and mucin-type O-glycosylated. There are also intracellular signaling pathways regulated by different post-translational modifications, including O-GlcNAcylation, which promote adequate responses to extracellular stimuli and signaling transduction. Herein, we provide an overview of N-glycosylation and O-glycosylation, including O-GlcNAcylation, and their role at different levels such as reception of signal, signal transduction, and exogenous molecules or agonists, which stimulate the heart and vascular wall cells with effects in different conditions, like the physiological status, ischemia/reperfusion, exercise, or during low-grade inflammation in diabetes and aging. Furthermore, mutations of glycosyltransferases and receptors are associated with development of cardiovascular diseases. The knowledge on glycosylation and its effects could be considered biochemical markers and might be useful as a therapeutic tool to control cardiovascular diseases.