Ser 16 -, but not Thr 17 -phosphorylation of phospholamban influences frequency-dependent force generation in human myocardium

Brixius, Klara; Wollmer, A; Bölck, Birgit; Mehlhorn, Uwe; Schwinger, Robert H. G.

doi:10.1007/s00424-003-1163-3

Cited by 31 publications

(15 citation statements)

References 36 publications

(42 reference statements)

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“…However, in the MOD phenotype, expression of NCX‐1 was increased and phosphorylation of phospholamban at S16 was decreased relative to sham and the other phenotypes (Figure 6A). While LVEF was preserved in the MOD phenotype, increases in NCX‐1 and decreased phospholamban phosphorylation are characteristic of humans with and experimental models of overt systolic HF 25, 26, 27, 28, 29…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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“…Limited data exist on the regulation of SERCA2a from human sources, and all data are from explanted hearts at terminal end‐stage HF, that is, a substantially different cohort than the current patients. Notwithstanding this, controversies exist regarding regulation of SERCA2a proteins, where several reports show no change of SERCA2a protein in HF,14, 15, 16, 17, 18, 19, 20 and others show reduced protein levels of SERCA2a 21, 22, 23. Despite the controversies on the extent of SERCA2a protein regulation in human HF, a clinical trial with the aim of increasing the SERCA2a protein levels in patients with HF was designed using recombinant adeno‐associated virus Serotype 1/SERCA2a;24 the initial data from the clinical Phase 1 trial reported promising results,25 but the continued Phase 2b trial failed to improve the clinical course of patients with HF and reduced EF 26.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of both the protein kinase A (PKA) site Ser‐16 and the CaMKII site Thr‐17 relieves the PLB inhibition of SERCA2 and thus increases its capacity to remove cytosolic Ca 2+ . Although reduced PLB phosphorylation is regarded as an important mechanism of lower SERCA2a activity in HF, conflicting results exist from both animal models and the limited work done in human HF; human data from explanted dilated cardiomyopathy hearts with terminal HF found both Ser‐16 and Thr‐17 phosphorylations of PLB to be reduced,15, 16 but a later report found only Ser‐16, but not Thr‐17, phosphorylation to be reduced 17…”

Section: Discussionmentioning

confidence: 99%

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

et al. 2018

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AimsCellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end‐stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post‐myocardial‐infarction (MI) patients at mid‐stage of HF.Methods and resultsNine MI patients and eight control patients without MI (non‐MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non‐MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+, lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse‐tubule density (−35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (−26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine‐16 and threonine‐17 in MI provides further mechanisms to the reduced function.ConclusionsDepressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid‐stage of post‐MI HF.

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“…Second, it is unknown whether EPAC-regulated Ca 2+ homeostasis is important for cardiac function and arrhythmogenesis under physiological conditions. Third, it remains unknown whether EPAC regulates PLN phosphorylation on serine-16 in addition to threonine-17, which is known to be a major regulator of Ca 2+ cycling in the heart and closely associated not only with an increase in cardiac function (16,17,56,57), but also with arrhythmia and cardiomyopathy after chronic catecholamine infusion, aortic banding, or ischemia (18,20,21). We thus generated Epac1 KO and Epac2 KO in addition to silencing EPAC1 with siRNA and selectively inhibiting PKA with Ad-PKI-GFP in cardiac myocytes.…”

Section: Discussionmentioning

confidence: 99%

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Okumura¹,

Fujita²,

Cai³

et al. 2014

J. Clin. Invest.

148

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PKA phosphorylates multiple molecules involved in calcium (Ca 2+ ) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca 2+ storage and the magnitude of Ca 2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKCε. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol-and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.

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Ser 16 -, but not Thr 17 -phosphorylation of phospholamban influences frequency-dependent force generation in human myocardium

Cited by 31 publications

References 36 publications

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

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