1.Cardiomyocyte-specific long noncoding RNA Trdn-as induces mitochondrial calcium overload by promoting the m6A modification of calsequestrin 2 in diabetic cardiomyopathy.
Xiaohan LI ; Ling LIU ; Han LOU ; Xinxin DONG ; Shengxin HAO ; Zeqi SUN ; Zijia DOU ; Huimin LI ; Wenjie ZHAO ; Xiuxiu SUN ; Xin LIU ; Yong ZHANG ; Baofeng YANG
Frontiers of Medicine 2025;19(2):329-346
Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca2+ overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, D830005E20Rik (Trdn-as), in DCM. Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, Trdn-as induced Ca2+ overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of Trdn-as. Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA, thereby enhancing the m6A modification of Casq2. This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression. When Casq2 was knocked down, the promoting effects of Trdn-as on Ca2+ overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.
Animals
;
Diabetic Cardiomyopathies/pathology*
;
RNA, Long Noncoding/genetics*
;
Myocytes, Cardiac/metabolism*
;
Mice
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Calsequestrin/genetics*
;
Calcium/metabolism*
;
Male
;
Sarcoplasmic Reticulum/metabolism*
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Methyltransferases/metabolism*
;
Mice, Inbred C57BL
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Mitochondria, Heart/metabolism*
;
Disease Models, Animal
;
Mitochondria/metabolism*
2.Investigation of Catecholaminergic Polymorphic Ventricular Tachycardia Children in China: Clinical Characteristics, Delay to Diagnosis, and Misdiagnosis.
He JIANG ; Xiao-Mei LI ; Hai-Yan GE ; Yi ZHANG ; Hai-Ju LIU ; Mei-Ting LI
Chinese Medical Journal 2018;131(23):2864-2865
Adolescent
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Calsequestrin
;
genetics
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Child
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Child, Preschool
;
China
;
Diagnostic Errors
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Female
;
Humans
;
Male
;
Tachycardia, Ventricular
;
diagnosis
3.A Novel mutation of F189L in CASQ2 in families with catecholaminergic polymorphic ventricular tachycardia.
Qian-qian LIU ; Carlos OBERTI ; Xian-qin ZHANG ; Tie KE ; Teng ZHANG ; Melvin SCHEINMAN ; Da-yi HU ; Qing Kenneth WANG
Chinese Journal of Medical Genetics 2008;25(3):334-337
OBJECTIVETo identify mutations and variants in CASQ2 gene in 27 CPVT patients/family members.
METHODSMutational analysis was performed with direct DNA sequence analysis. The frequency of an identified CASQ2 variant was determined using the Taqman genotyping assay.
RESULTSA novel heterozygous mutation, F189L, in CASQ2 gene was identified in one family with CPVT. This mutation occurred at the evolutionarily, highly conserved phenylalanine residue at codon 189, and was not present in 1400 control individuals. No other disease-causing mutations were identified in the CASQ2 gene.
CONCLUSIONA novel mutation of F189L in the CASQ2 gene was identified.
Calsequestrin ; genetics ; DNA Mutational Analysis ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Male ; Mutation ; Pedigree ; Tachycardia, Ventricular ; genetics ; Young Adult
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