Identification of key candidate genes and pathways revealing the protective effect of liraglutide on diabetic cardiac muscle by integrated bioinformatics analysis

Dong, Ying; Shi, Yan; Li, Guoyan; Wang, Minnan; Leng, Lei; Li, Qiang

doi:10.21037/atm.2020.01.94

Cited by 5 publications

(5 citation statements)

References 38 publications

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“…However, glucagon-like peptide 1 (GLP-1) agonists are shown to exacerbate heart failure or have no significant cardiovascular outcome in T2DM patients (371). GLP-1 agonists are cardioprotective in DCM rodent models by inhibiting UPR ER signaling and ERmediated apoptosis (368)(369)(370)381). Therefore, these drugs fall short of mitigating heart failure in diabetes patients, possibly due to inhibition of adaptive ERSR.…”

Section: Targeting the Upr Ermentioning

confidence: 99%

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Kaur

Raja

Ruiz-Velasco

et al. 2020

Front. Cardiovasc. Med.

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Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.

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Section: Targeting the Upr Ermentioning

confidence: 99%

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Kaur

Raja

Ruiz-Velasco

et al. 2020

Front. Cardiovasc. Med.

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show abstract

“…This analytical strategy has also been applied in other studies. Dong et al performed an integrated bioinformatics analysis and revealed key candidate genes and pathways that may be associated with the protective effect of liraglutide on diabetic cardiac muscle [ 31 ]. As HMGCS2 has been found to exert important actions in the cardiomyocytes, we further selected this gene for the subsequent functional study.…”

Section: Discussionmentioning

confidence: 99%

HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress

et al. 2022

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Diabetic cardiomyopathy (DCM) is a diabetic mellitus-related complications and progression of DCM may eventually lead to heart failure, while mechanisms related to DCM pathophysiology remain unclear. The study was undertaken to identify possible hub genes associated with DCM progression through bioinformatics analysis and to validate the role of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in DCM progression using a cellular model of high glucose (HG)-induced DCM. The common differentially expressed genes (DEGs) between GSE173884 and GSE161827 were used for PPI network analysis. Our results identified 17 common DEGs between GSE173384 and GSE161827. Further analysis of the protein–protein interaction network identified nine hub genes and HMGCS2. The in vitro functional assays showed that HG induced up-regulation of HMGCS2, suppressed cardiomyocyte viability, enhanced apoptosis, inflammation, and oxidative stress of cardiomyocytes. Gain-of-function assays showed that HMGCS2 overexpression reduced cell viability, increased apoptosis, caspase-3/-9 activity, up-regulated interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) expression, decreased superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase expression, increased malondialdehyde (MDA) content, and reactive oxygen species (ROS) level but inhibited total antioxidant activity, SOD activity, CAT activity, and glutathione content in cardiomyocytes. Rescue experiments demonstrated HMGCS2 silence attenuated HG-induced decrease in cardiomyocyte viability and increase in cardiomyocyte apoptosis, inflammation, and oxidative stress. All in all, our study identified HMGCS2 as a hub gene in DCM pathophysiology and further functional studies indicated that HMGCS2 may aggravate DCM progression by reducing cardiomyocyte viability, increasing cardiomyocyte apoptosis, and promoting inflammation and oxidative stress in cardiomyocytes.

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“…The downregulation of the ACTN2 gene in women with GDiM, in comparison to continent–diabetic women, may be linked to the development of myopathy. Previous studies have shown that the endogenous expression of ACTN2 changes in skeletal muscles in response to various cellular environments, and is linked to a diabetic hypertrophic cardiomyopathy in cardiac muscle [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of Rectus Abdominis Muscle in Women with Gestational Diabetes-Induced Myopathy: Characterization of Pathophysiology and Potential Muscle Biomarkers of Pregnancy-Specific Urinary Incontinence

Alves

Oliveira

Reyes

et al. 2022

IJMS

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Gestational diabetes mellitus (GDM) is recognized as a “window of opportunity” for the future prediction of such complications as type 2 diabetes mellitus and pelvic floor muscle disorders, including urinary incontinence and genitourinary dysfunction. Translational studies have reported that pelvic floor muscle disorders are due to a GDM-induced-myopathy (GDiM) of the pelvic floor muscle and rectus abdominis muscle (RAM). We now describe the transcriptome profiling of the RAM obtained by Cesarean section from GDM and non-GDM women with and without pregnancy-specific urinary incontinence (PSUI). We identified 650 genes in total, and the differentially expressed genes were defined by comparing three control groups to the GDM with PSUI group (GDiM). Enrichment analysis showed that GDM with PSUI was associated with decreased gene expression related to muscle structure and muscle protein synthesis, the reduced ability of muscle fibers to ameliorate muscle damage, and the altered the maintenance and generation of energy through glycogenesis. Potential genetic muscle biomarkers were validated by RT-PCR, and their relationship to the pathophysiology of the disease was verified. These findings help elucidate the molecular mechanisms of GDiM and will promote the development of innovative interventions to prevent and treat complications such as post-GDM urinary incontinence.

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Identification of key candidate genes and pathways revealing the protective effect of liraglutide on diabetic cardiac muscle by integrated bioinformatics analysis

Cited by 5 publications

References 38 publications

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress

Transcriptomic Profiling of Rectus Abdominis Muscle in Women with Gestational Diabetes-Induced Myopathy: Characterization of Pathophysiology and Potential Muscle Biomarkers of Pregnancy-Specific Urinary Incontinence

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