Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

Kirchhefer, Uwe; Brekle, Christiane; Eskandar, John; Isensee, Gunnar; Kučerová, Dana; Müller, Frank; Pinet, Florence; Schulte, Jan S.; Seidl, Matthias D.; Boknı́k, Peter

doi:10.1074/jbc.m114.598938

Cited by 52 publications

(49 citation statements)

References 52 publications

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“…Contrary to our results, the deficiency of B56α (another regulatory of PP2A), which is an autoinhibitor of cardiac PP2A activity, resulted in increased PP2A activity [13]. However, some studies revealed that B56α deficiency may decrease PP2A activity too, and overexpression of B56α enhanced PP2A activity in the heart [13,20]. It is possible that different regulatory subunits of PP2A have different influences in PP2A activity.…”

Section: Discussioncontrasting

confidence: 97%

Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

Yang

Gan

et al. 2016

IJMS

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Protein phosphatase 2 regulatory subunit B, alpha (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), is a major serine/threonine phosphatase that regulates crucial function in development and growth. Previous research has implied that PPP2R3A was involved in heart failure, and PR130, the largest transcription of PPP2R3A, functioning in the calcium release of sarcoplasmic reticulum (SR), plays an important role in the excitation-contraction (EC) coupling. To obtain a better understanding of PR130 functions in myocardium and cardiac development, two pr130-deletion zebrafish lines were generated using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system. Pr130-knockout zebrafish exhibited cardiac looping defects and decreased cardiac function (decreased fractional area and fractional shortening). Hematoxylin and eosin (H&E) staining demonstrated reduced cardiomyocytes. Subsequent transmission electron microscopy revealed that the bright and dark bands were narrowed and blurred, the Z- and M-lines were fogged, and the gaps between longitudinal myocardial fibers were increased. Additionally, increased apoptosis was observed in cardiomyocyte in pr130-knockout zebrafish compared to wild-type (WT). Taken together, our results suggest that pr130 is required for normal myocardium formation and efficient cardiac contractile function.

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Section: Discussioncontrasting

confidence: 97%

Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

Yang

Gan

et al. 2016

IJMS

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“…Physiologically, these phenotypes resulted in reduced heart rate, heart rate variability, conduction abnormalities and resistance to catecholamine-induced arrhythmias, highlighting the potential of targeting specific PP2A subunits therapeutically [21]. Interestingly, a second study has shown that acute overexpression of B56α may lead to increased PP2A activity in the cytoplasm and myofilament fractions of heart lysates [76]. This may indicate differential functions of B56α depending on cellular compartment that may be facilitated by the phosphorylation of B56α at Ser41 (modifies PP2A-C-B56α affinity) [43,76].…”

Section: Pp2a Regulation In Diseasementioning

confidence: 99%

“…Interestingly, a second study has shown that acute overexpression of B56α may lead to increased PP2A activity in the cytoplasm and myofilament fractions of heart lysates [76]. This may indicate differential functions of B56α depending on cellular compartment that may be facilitated by the phosphorylation of B56α at Ser41 (modifies PP2A-C-B56α affinity) [43,76]. B56α has also been implicated in the pathophysiology of “Ankyrin-B Syndrome”, as the loss of ankyrin-B function, essential to B56α localization, may lead to altered RyR2 phosphorylation and arrhythmia [43,77].…”

Section: Pp2a Regulation In Diseasementioning

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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“…This indicates that fibrosis selectively increases the phosphorylation level of troponin I. Szymanska et al reported that the responses to adrenergic stimulation differed between PLN and troponin I [28]. Kirchhefer et al reported that protein phosphatase 2A activity differed among RyR, PLN, and troponin I [29]. Kuo et al showed that reduced expression of polycystin 2, which senses fluid stress, increased the phosphorylation level of cardiac troponin I with a reduced phosphorylation level of PLN [30].…”

Section: Discussionmentioning

confidence: 99%

Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding

et al. 2017

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Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca2+ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.

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Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

Cited by 52 publications

References 52 publications

Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

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

Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding

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