Critical roles of junctophilin-2 in T-tubule and excitation–contraction coupling maturation during postnatal development

Chen, Biyi; Guo, Ang; Zhang, Caimei; Chen, Rong; Zhu, Yingke; Hong, Jiang; Kutschke, William; Zimmerman, Kathy; Weiß, Robert M.; Zingman, Leonid V.; Anderson, Mark E.; Wehrens, Xander H.T.; Song, Long‐Sheng

doi:10.1093/cvr/cvt180

Cited by 91 publications

(116 citation statements)

References 47 publications

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“…Myocardial expression of junctophilin‐2 and expression of α‐myosin heavy chain ( Myh6 ) were decreased in Velvet mice with significant valve dysfunction, findings that are also consistent with reversion to a fetal gene program (Figure 9C and 9D) 18. There was no significant increase in expression of collagen‐1a1 or collagen‐3a1 in myocardium from Velvet mice with valve dysfunction (Figure 9E and 9F).…”

Section: Resultssupporting

confidence: 65%

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Discovery of an Experimental Model of Unicuspid Aortic Valve

Weiß

Chu

Brooks

et al. 2018

JAHA

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BackgroundThe epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss‐of‐function mutation in epithelial growth factor receptor, which are Egfr Vel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy.Methods and ResultsAortic valves from Egfr Vel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional Egfr Vel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of Egfr Vel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in Egfr Vel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of Egfr Vel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in Egfr Vel/+ mice with aortic valve dysfunction, but not in Egfr Vel/+ mice with near‐normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups.ConclusionsA new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.

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Section: Resultssupporting

confidence: 65%

“…Adult mice that are subjected to acute severe pressure overload,18 and mice that acquire severe AS during adult life, develop LV systolic dysfunction or die shortly thereafter 11, 12. Humans who acquire severe AS during adult life usually develop symptoms within 2 years 26.…”

Section: Discussionmentioning

confidence: 99%

Discovery of an Experimental Model of Unicuspid Aortic Valve

Weiß

Chu

Brooks

et al. 2018

JAHA

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“…JPH2 overexpression had comparatively little impact on the t-system morphology similar to findings in Guo et al (2014). Detailed analysis showed an increase in longitudinal t-system connections (by ∼10%) which might result from the role of JPH2 in the development of the t-system (Chen et al, 2013;Reynolds et al, 2013), but importantly this does not lead to any detectable impact on Ca 2+ handling in intact myocytes. Taken together, the moderate effect on t-system architecture in conjunction with essentially normal Ca 2+ handling in JPH2-OE murine myocytes in a mouse model independently developed from that shown in Guo et al (2014) shows that these are robust observations that do not depend on details of the overexpression system, which is important when considering its therapeutic potential.…”

Section: Discussionmentioning

confidence: 68%

“…In cardiac muscle cells, the loss of JPH2 has previously been shown to play a major role in the organisation of the t-tubules Wei et al, 2010;Wu et al, 2014;Chen et al, 2013). In addition to control and JPH2-OE myocytes, JPH2-KD myocytes were also included as a sample with known changes in t-system properties .…”

Section: T-tubule System Changes In Cells With Altered Jph2mentioning

confidence: 99%

Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes

Munro

Jayasinghe

Wang

et al. 2016

Journal of Cell Science

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Signalling nanodomains requiring close contact between the plasma membrane and internal compartments, known as ‘junctions’, are fast communication hubs within excitable cells such as neurones and muscle. Here we have examined two transgenic murine models probing the role of junctophilin-2, a membrane tethering protein crucial for the formation and molecular organisation of sub-microscopic junctions in ventricular muscle cells of the heart. Quantitative single molecule localisation microscopy showed that junctions in animals producing above-normal levels of junctophilin-2 were enlarged, allowing the re-organisation of the primary functional protein within it, the ryanodine receptor (RyR). Although this change was associated with much enlarged RyR clusters that due to their size should be more excitable, functionally it caused a mild inhibition in the calcium signalling output of the junctions (calcium sparks). Analysis of the single molecule densities of both RyR and junctophilin-2 revealed an ∼3-fold increase in the junctophilin-2 to RyR ratio. This molecular rearrangement is compatible with direct inhibition of RyR opening by junctophilin-2 to intrinsically stabilise the calcium signalling properties of the junction and thus the contractile function of the cell.

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“…The development of these structures occurs later on in gestation and continues after birth until cardiomyocytes reach full maturity. The development and maturation of T-tubules has been described in animal models (Al-Qusairi and Laporte, 2011; Chen et al, 2013;Seki, 2003). The development of the heart of a human neonate presumably occurs via similar processes though with a longer duration due to developmental differences in humans and rodents.…”

Section: Characterisation Of the Human Fetal Heartmentioning

confidence: 99%

The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts

Schultz

Hasan

Alvarez-Laviada

et al. 2016

Progress in Biophysics and Molecular Biology

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Critical roles of junctophilin-2 in T-tubule and excitation–contraction coupling maturation during postnatal development

Abstract: Our data identify a critical role for JP2 in T-tubule and excitation-contraction coupling maturation during development.

Cited by 91 publications

References 47 publications

Discovery of an Experimental Model of Unicuspid Aortic Valve

Discovery of an Experimental Model of Unicuspid Aortic Valve

Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes

The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts

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