Heart Failure Induces Significant Changes in Nuclear Pore Complex of Human Cardiomyocytes

Tarazón, Estefanía; Rivera, Miguel; Roselló‐Lletí, Esther; Molina-Navarro, María Micaela; Sánchez‐Lázaro, Ignacio; España, Francisco; Montero, José; Lago, Francisca; González-Juanatey, José Ramón; Portolés, Manuel

doi:10.1371/journal.pone.0048957

Cited by 42 publications

(34 citation statements)

References 32 publications

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“…While our zebrafish data indicate a potential role for nucleoporins in cardiovascular development, these proteins are likely to function in adult heart as well, and ultimately, it is difficult to correlate phenotypes seen in fish with phenotypes one would see in a human. 38 …”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Haskell

Jensen²,

Samsa³

et al. 2017

Circ Cardiovasc Genet

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Background The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset. Methods and Results We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases, and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes NUP37, NUP43, and NUP188, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene SYNE1 in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce SYNE1, NUP37, and NUP43 gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a SYNE1 splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope. Conclusions These data expand the repertoire of pathogenic variants associated with cardiovascular disease, and validate the diagnostic and research utility of whole exome sequencing. We identify NUP37, NUP43, and NUP188 as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Haskell

Jensen²,

Samsa³

et al. 2017

Circ Cardiovasc Genet

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“…EXP-1 mediates the nuclear export of proteins, rRNA, snRNA, and some mRNAs. Previous studies in patients with ischemic cardiomyopathy showed elevated expression levels of both EXP-1 mRNA and protein, and interestingly, these levels were inversely related with ejection fraction and positively correlated with LVESD and LVEDD [5, 6], i.e . higher EXP-1 expression is linked with LV function impairment.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that several molecules that participate in nuclear-cytoplasmic transport (Exportin-1 [EXP-1], IMP-β3, Nup160) are intimately related to a reduced left ventricular (LV) function in human HF. It has been found the transcriptomic signature of these alterations and has been identified that changes in gene expression, specifically of XPO1 that encodes EXP-1, were highly related to LV dysfunction in patients with HF of ischemic etiology [5, 6].…”

Section: Introductionmentioning

confidence: 99%

XPO1 gene therapy restores cardiac function in rats with chronic induced myocardial infarction

García‐Manzanares

Gil-Cayuela

Martínez‐Dolz

et al. 2019

Preprint

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Background: In previous studies, we showed that several nuclear-cytoplasmic transport molecules were closely related to ventricular dysfunction in human heart failure. Particularly, the transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in heart failure patients of ischemic etiology. Therefore, we hypothesized that in a rat model of myocardial infarction treated with AAV9-shXPO1, an improvement in the ventricular function after a follow-up period may be observed.Methods: We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n=10), five of them received AAV9-shXPO1 treatment after four months and the other five infarcted rats did not receive any treatment. For non-failing controls, healthy Sham rats (n=5) received the placebo AAV9-scramble. Serial echocardiographic assessment was performed before, as well as, two and five months after intravenous injection.Results: AAV9-shXPO1-treated rats showed improved fractional shortening (16.8 ± 2.8 vs 24.6 ± 4.1%, P<0.05) and LV systolic (5.10 ± 0.79 vs 3.52 ± 0.88mm, P<0.05) and diastolic (6.17 ± 0.95 vs 4.70 ± 0.93mm, P<0.05) diameters when comparing measurements obtained before and five months after AAV9 injection. We did not observe this improvement in untreated infarcted rats. Furthermore, EXP-1 levels in rats heart, brain, skeletal muscle, and liver were determined by western-blot and compared to controls in AAV9-shXPO1-treated rats. Lower levels of EXP-1 in cardiac tissue were observed (P<0.05).Discussion: At five months follow-up, ischemic AAV9-shXPO1-treated rats showed partial recovery of LV myocardial function. No secondary symptoms attributable to AAV9-shXPO1 were observed in skeletal muscle, liver and brain.

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“…Specifically the transmembrane nucleoporin NDC1, the scaffold nucleoporin Nup160, and the nuclear basket nucleoporin Nup153 are increased in hearts of patients with ischemic and dilated cardiomyopathy, while Nup93 was increased only in dilated heart patients. NDC1 was also shown to be mislocalized in cardiomyocytes from both ischemic and dilated hearts [162]. Supporting these data, a point mutation in the scaffold nucleoporin Nup155 was sufficient to delocalize the nucleoporin from the NPC, which led to early sudden death due to atrial fibrillation.…”

Section: Npcs In Other Disordersmentioning

confidence: 91%

The roles of the nuclear pore complex in cellular dysfunction, aging and disease

Sakuma

D’Angelo

2017

Seminars in Cell & Developmental Biology

110

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The study of the Nuclear Pore Complex (NPC), the proteins that compose it (nucleoporins), and the nucleocytoplasmic transport that it controls has revealed an unexpected layer to pathogenic disease onset and progression. Recent advances in the study of the regulation of NPC composition and function suggest that the precise control of this structure is necessary to prevent diseases from arising or progressing. Here we discuss the role of nucleoporins in a diverse set of diseases, many of which directly or indirectly increase in occurrence and severity as we age, and often shorten the human lifespan. NPC biology has been shown to play a direct role in these diseases and therefore in the process of healthy aging.

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Heart Failure Induces Significant Changes in Nuclear Pore Complex of Human Cardiomyocytes

Cited by 42 publications

References 32 publications

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

XPO1 gene therapy restores cardiac function in rats with chronic induced myocardial infarction

The roles of the nuclear pore complex in cellular dysfunction, aging and disease

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