Understanding Vascular Diseases: Lessons From Premature Aging Syndromes

Ikeda, Yuichi; Kumagai, Hidetoshi; Motozawa, Yoshihiro; Suzuki, Jun; Akazawa, Hiroshi; Komuro, Issei

doi:10.1016/j.cjca.2015.12.003

Cited by 10 publications

(15 citation statements)

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“…Many characteristics of normal aging appear to be accelerated in individuals with dominant mutations in the LMNA gene encoding A‐type lamins (Ahmed, Ikram, Bibi & Mir, 2017; Apte, Stick & Radmacher, 2017; Cenni et al., 2017; Ikeda et al., 2016; Scaffidi & Misteli, 2006). These include cardiac diseases with a broad range of arrhythmic disturbances, left ventricle dysfunction, and heart failure that show increasing penetrance with age (Captur et al., 2017; Liang, Grogan & Ackerman, 2016).…”

Section: Introductionmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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SummaryMutations in the human LMNA gene cause a collection of diseases known as laminopathies. These include myocardial diseases that exhibit age‐dependent penetrance of dysrhythmias and heart failure. The LMNA gene encodes A‐type lamins, intermediate filaments that support nuclear structure and organize the genome. Mechanisms by which mutant lamins cause age‐dependent heart defects are not well understood. To address this issue, we modeled human disease‐causing mutations in the Drosophila melanogaster Lamin C gene and expressed mutant Lamin C exclusively in the heart. This resulted in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Within cardiac cells, mutant Lamin C aggregated in the cytoplasm, the CncC(Nrf2)/Keap1 redox sensing pathway was activated, mitochondria exhibited abnormal morphology, and the autophagy cargo receptor Ref2(P)/p62 was upregulated. Genetic analyses demonstrated that simultaneous over‐expression of the autophagy kinase Atg1 gene and an RNAi against CncC eliminated the cytoplasmic protein aggregates, restored cardiac function, and lengthened lifespan. These data suggest that simultaneously increasing rates of autophagy and blocking the Nrf2/Keap1 pathway are a potential therapeutic strategy for cardiac laminopathies.

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Section: Introductionmentioning

confidence: 99%

Increasing autophagy and blocking Nrf2 suppress laminopathy‐induced age‐dependent cardiac dysfunction and shortened lifespan

et al. 2018

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“…Accumulation of progerin leads to nuclear structure changes including membrane blebs and altered chromatin organization (Ikeda et al 2016;Navarro et al 2006). …”

Section: Hutchinson-gilford Progeria Syndromementioning

confidence: 99%

“…The classical LMNA mutation at codon 608 (G>G) does not affect protein coding, but instead causes alternative splicing of the LNMA transcript that results in the production of a truncated pre-Lamin A protein (known as 'progerin' and 'Lamin A-Δ50') (Eriksson et al 2003;Ikeda et al 2016). The mutant pre-Lamin A, which lacks a ZMPSTE24 cleavage site, cannot be properly post-translationally processed and consequently, remains farnesylated and nuclear membrane-bound (Ikeda et al 2016;Navarro et al 2006). …”

Section: Hutchinson-gilford Progeria Syndromementioning

confidence: 99%

“…D r a f t 8 ageing and that are typified by vascular pathologies (Ikeda et al 2016). These syndromes arise from single-gene mutations that perturb nuclear structure or DNA repair, respectively, ultimately resulting in genomic instability (Ikeda et al 2016).…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…These syndromes arise from single-gene mutations that perturb nuclear structure or DNA repair, respectively, ultimately resulting in genomic instability (Ikeda et al 2016). …”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

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