Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations

Liu, Ruijie; Correll, Robert N.; Davis, Jennifer; Vagnozzi, Ronald J.; York, Allen J.; Sargent, Michelle A.; Nairn, Angus C.; Molkentin, Jeffery D.

doi:10.1016/j.yjmcc.2015.08.018

Cited by 46 publications

(65 citation statements)

References 55 publications

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“…For analysis of longitudinal strain and diastolic function by echocardiography, a Vevo 2100 instrument with 18-38 MHz transducer (VisualSonics) was used as previously described (59). Longitudinal B-mode loops of 300 frames each were analyzed using VevoLAB speckle-based tracking (VisualSonics) to determine average longitudinal strain across the left ventricle.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Khalil¹,

Kanisicak²,

Prasad³

et al. 2017

Journal of Clinical Investigation

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704

551

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reverse transcribed using random oligo-dT primers and a Verso cDNA Synthesis Kit (Thermo Fisher, AB1453) according to the manufacturer's instructions. Real-time PCR was performed using SsoAdvanced SYBR Green (Bio-Rad, 6090), and Rpl7 expression was used for normalization. The following primer sets were used to identify transcripts: collagen 1a1, 5′-AATGGCACGGCTGTGTGCGA and 5′-AACGGGTCCCCTTG-GGCCTT; collagen 3a1, 5′-TCCCCTGGAATCTGTGAATC and 5′-TGAGTCGAATTGGGGAGAAT; periostin, 5′-ACGGAGCTCAGG-GCTGAAGATG and 5′-GTTTGGGCCCTGATCCCGAC.Cell death analysis. At 90% confluence, primary skin fibroblasts were treated with 200 nM staurosporine for 36 hours or vehicle (DMSO). Cell death was determined by the Muse Count & Viability Assay (Millipore, MCH100102) as previously described (62). Briefly, the medium was collected with the trypsin-liberated cells, which were centrifuged and washed twice with PBS and then incubated with the Muse Count & Viability reagent. The cells were then quantified on a Muse cell analyzer (Millipore) at 5,000 counts per sample.Statistics. One-way ANOVA with post hoc Tukey's honest significant difference (HSD) or Student's t test was used to determine statistical significance, depending on the type of data analyzed and number of comparisons. P values of less than 0.05 were considered statistically significant. Averaged data are presented with SEM to indicate variability.Study approval. Mice were observed daily and cages changed weekly by certified veterinary technicians at Cincinnati Children's Hospital Medical Center. Mice were also closely assessed for their well-being, monitored by adequate physical activity and food intake on a daily basis. Housing conditions and husbandry conformed to AAALAC standards as well as the standard guidelines from the NIH Office of Laboratory Animal Welfare (http://grants.nih.gov/grants/olaw/animal_use. htm). The institution also retains ongoing certification by AAALAC.

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Section: Methodsmentioning

confidence: 99%

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Khalil¹,

Kanisicak²,

Prasad³

et al. 2017

Journal of Clinical Investigation

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704

551

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“…Adult mouse ventricular myocytes were isolated from whole hearts on a hanging apparatus with a solution containing liberase blendzyme (Roche, #05401151001) as previously described. 31 Following isolation, cardiac myocytes were plated on laminin-coated dishes and cultured in medium 199 (Corning, 10-060-CV). Cardiac myocyte length and width were measured with NIH ImageJ software on phase contrast images of fixed cells.…”

Section: Methodsmentioning

confidence: 99%

DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling

Liu

Berlo

York

et al. 2016

Circulation Research

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Rationale Mitogen-activated protein kinase (MAPK) signaling regulates the growth response of the adult myocardium in response to increased cardiac workload or pathologic insults. The dual-specificity phosphatases (DUSPs) are critical effectors that dephosphorylate the MAPKs to control the basal tone, amplitude and duration of MAPK signaling. Objective To examine the dual-specificity phosphatase 8 (DUSP8) as a regulator of MAPK signaling in the heart and its impact on ventricular and cardiac myocyte growth dynamics. Methods and Results Dusp8 gene-deleted mice as well as transgenic mice with inducible expression of DUSP8 in the heart were used here to investigate how this MAPK-phosphatase might regulate intracellular signaling and cardiac growth dynamics in vivo. Dusp8 gene-deleted mice were mildly hypercontractile at baseline with a cardiac phenotype of concentric ventricular remodeling, which protected them from progressing towards heart failure in two surgery-induced disease models. Cardiac-specific overexpression of DUSP8 produced spontaneous eccentric remodeling and ventricular dilation with heart failure. At the cellular level, adult cardiac myocytes from Dusp8 gene-deleted mice were thicker and shorter, while DUSP8 overexpression promoted cardiac myocyte lengthening with a loss of thickness. Mechanistically, activation of extracellular signal-regulated kinases 1/2 (ERK1/2) were selectively increased in Dusp8 gene-deleted hearts at baseline as well as following acute pathologic stress stimulation, while p38 MAPK and c-Jun N-terminal kinases were unaffected. Conclusions These results indicate that DUSP8 controls basal and acute stress-induced ERK1/2 signaling in adult cardiac myocytes that then alters the length-width growth dynamics of individual cardiac myocytes, which further alters contractility, ventricular remodeling and disease susceptibility.

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“…Further diversity is achieved through alternative splicing of PPP1CA and PP1CC . Each resultant isoform is suggested to have cell- and tissue-specific expression [16,23]. The activity of PP1 is further regulated through ~200 regulatory subunits/proteins that combine with the catalytic PP1C subunit to modulate holoenzyme activity [24].…”

Section: Protein Phosphatase Familiesmentioning

confidence: 99%

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Lubbers

Mohler

2016

Journal of Molecular and Cellular Cardiology

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Reversible protein phosphorylation is central to a variety of cardiac processes including excitation-contraction coupling, Ca2+ handling, cell metabolism, myofilament regulation, and cell-cell communication. While kinase pathways linked with elevated adrenergic signaling have been a major focus for the cardiovascular field over the past half century, new findings support the critical role of protein phosphatases in both health and disease. Protein phosphatase 2A (PP2A) is a central cardiac phosphatase that regulates diverse myocyte functions through a host of target molecules. Notably, multiple mechanisms have evolved to dynamically tune PP2A function, including modulation of the composition, phosphorylation, methylation, and localization of PP2A holoenzyme populations. Further, aberrations in this regulation of PP2A function may contribute to cardiac pathophysiology. In summary, PP2A is a critical regulatory molecule in both health and disease, with a myriad of targets in heart. Based on their unique structure, localization, and regulatory properties, PP2A subunits represent exciting therapeutic targets to modulate altered adrenergic signaling in cardiovascular disease.

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Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations

Cited by 46 publications

References 55 publications

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

DUSP8 Regulates Cardiac Ventricular Remodeling by Altering ERK1/2 Signaling

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

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