Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

Gerbino, Andrea; Bottillo, Irene; Milano, Serena; Lipari, Martina; Zio, Roberta De; Morlino, Silvia; Mola, Maria Grazia; Procino, Giuseppe; Re, Federica; Zachara, Elisabetta; Grammatico, Paola; Svelto, María; Carmosino, Monica

doi:10.1159/000485651

Cited by 15 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pharmacological activation of WNT/β-catenin signaling using 6-bromoindirubin-3′-oxime (BIO), a GSK3-β inhibitor, restored connexin 43, Wnt-1 and β-catenin expressions and improved cardiac functions of Lmna H222P / H222P mice [ 102 ]. Similar results were observed in HL-1 cardiomyocytes transfected with LMNA p.Asp243Glyfs*4 mutant, where decreased connexin 43 level was restored by lithium treatment, another well-known GSK3 inhibitor [ 103 ].…”

Section: Therapies For Striated Muscle Laminopathiessupporting

confidence: 75%

Preclinical Advances of Therapies for Laminopathies

Benarroch

Cohen

Atalaia

et al. 2021

JCM

View full text Add to dashboard Cite

Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.

show abstract

Section: Therapies For Striated Muscle Laminopathiessupporting

confidence: 75%

Preclinical Advances of Therapies for Laminopathies

Benarroch

Cohen

Atalaia

et al. 2021

JCM

View full text Add to dashboard Cite

show abstract

“…When UPR cannot restore ER homeostasis, PERK activation leads to eIF2α phosphorylation, which selectively induces a transcription factor called ATF4. ATF4 enhances the expression of CCAAT/enhancer-binding protein homologous protein (CHOP), which exerts pro-apoptotic effects [35, 36]. In several cell lines, ER stress has been found to be activated following UA exposure [37-39] and was reported to be involved in UA-induced apoptosis in one of these studies [39].…”

Section: Discussionmentioning

confidence: 99%

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

Yan

Chen

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Hyperuricemia is associated with an increased risk for multiple cardiovascular diseases, but the underlying mechanisms remain largely elusive. Calpain-1 is a protease that is implicated in several pathological conditions that affect the heart. The aim of this current study was to test the effects of uric acid (UA) on cardiomyocyte survival and cardiac function and to investigate the role of calpain-1 in the UA-induced effects in the heart and their underlying mechanisms. Methods: In vivo, hyperuricemia was induced by oxonic acid (OA) administration in Sprague-Dawley rats for 16 weeks; TUNEL staining was used to identify apoptotic cells. Left ventricular (LV) sections were stained with Sirius Red to evaluate interstitial fibrosis. Cardiac catheterization was performed to evaluate cardiac function. In vitro, cultured H9c2 cells were incubated with different UA concentrations. MTT assays and flow cytometry were used to evaluate cell viability and apoptosis. All related gene expression levels were analyzed by quantitative real-time PCR (qRT-PCR), and all protein expression levels were analyzed by western blotting. Results: Hyperuricemia induction in vivo resulted in cellular apoptosis, interstitial fibrosis and diastolic dysfunction in the rat hearts, as well as increased activation of calpain-1 and endoplasmic reticulum (ER) stress, while allopurinol treatment mitigated the above changes. UA administration in vitro increased apoptosis and decreased H9c2 cell viability in a dose-dependent manner. Increased activation of calpain-1 and ER stress was also observed in the groups with high UA levels. Calpain-1 siRNA and the calpain inhibitor CI-III alleviated UA-induced ER stress and apoptosis, while inhibiting ER stress by tauroursodeoxycholic acid (TUDCA) mitigated UA-induced apoptosis without affecting calpain-1 expression or activity. Conclusions: These findings suggest that UA induces cardiomyocyte apoptosis through activation of calpain-1 and ER stress. These results may provide new insights into the mechanisms of hyperuricemia-associated cardiovascular risks and hopefully identify new treatment targets.

show abstract

“…Therefore, we evaluated SERCA2 activity as the passive Ca 2+ permeability of the ER when the Ca 2+ -ATPase is blocked by CPA. This is a well-known experimental procedure that will increase cytosolic Ca 2+ level as index of ER Ca 2+ levels [11, 12]. In Fig.…”

Section: Resultsmentioning

confidence: 99%

DP71 and SERCA2 alteration in human neurons of a Duchenne muscular dystrophy patient

et al. 2019

Self Cite

View full text Add to dashboard Cite

Cognitive deficit has been identified in one third of patients affected by Duchenne Muscular Dystrophy, primarily attributed to loss of the short Dp71 dystrophin, the major brain dystrophin isoform. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in human neurons obtained by differentiation from induced pluripotent stem cell line of a patient affected by cognitive impairment. We found structural and molecular alterations in both pluripotent stem cell and derived neurons, reduced Dp71 expression, and a Ca2+ cytoplasmic overload in neurons coupled with increased expression of the SERCA2 pump in the dystrophic neurons. These results suggest that the reduction of Dp71 protein in the Duchenne muscular dystrophy neurons leads to alterations in SERCA2 and to elevated cytosolic Ca2+ concentration with consequent potential disruption of the dystrophin proteins and Dp71-associated proteins.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1125-5) contains supplementary material, which is available to authorized users.

show abstract

Functional Characterization of a Novel Truncating Mutation in Lamin A/C Gene in a Family with a Severe Cardiomyopathy with Conduction Defects

Cited by 15 publications

References 40 publications

Preclinical Advances of Therapies for Laminopathies

Preclinical Advances of Therapies for Laminopathies

Uric Acid Induces Cardiomyocyte Apoptosis via Activation of Calpain-1 and Endoplasmic Reticulum Stress

DP71 and SERCA2 alteration in human neurons of a Duchenne muscular dystrophy patient

Contact Info

Product

Resources

About