Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts

El‐Armouche, Ali; Pamminger, Torsten; Ditz, Diana; Zolk, Oliver; Eschenhagen, Thomas

doi:10.1016/j.cardiores.2003.11.005

Cited by 127 publications

(104 citation statements)

References 25 publications

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“…7). Moreover, the PKA-dependent inhibitory regulator of PP1, inhibitor-1, reduced expression of which in failing ventricles has been suggested to contribute to reduced protein phosphorylation (20), was also not different between the two groups of cells.…”

Section: H387mentioning

confidence: 81%

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Bond

Bryant

Watson

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Bond RC, Bryant SM, Watson JJ, Hancox JC, Orchard CH, James AF. Reduced density and altered regulation of rat atrial L-type Ca 2ϩ current in heart failure. Am J Physiol Heart Circ Physiol 312: H384 -H391, 2017. First published December 6, 2016; doi:10.1152/ ajpheart.00528.2016.-Constitutive regulation by PKA has recently been shown to contribute to L-type Ca 2ϩ current (ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaL in heart failure. The hypothesis that downregulation of atrial ICaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, Nϭ10) or equivalent sham-operation (Sham, Nϭ12). Left atrial myocytes were isolated~18 wk postsurgery and whole cell currents recorded (holding potentialϭ-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to ϩ50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were~1.67-fold greater than Sham (P Յ 0.0001). Maximal ICaL conductance (Gmax) was downregulated more than 2-fold in CAL vs. Sham myocytes (P Ͻ 0.0001). Norepinephrine (1 mol/l) increased Gmax Ͼ50% more effectively in CAL than in Sham so that differences in ICaL density were abolished. Differences between CAL and Sham Gmax were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaL downregulation. Treatment with either H-89 (10 mol/l) or AIP (5 mol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL. Expression of the L-type ␣1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure. NEW & NOTEWORTHY Whole cell recording of L-type Ca 2ϩcurrents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without change in channel subunit expression and associated with altered phosphorylation independent of protein kinase A. atrial remodeling; coronary artery ligation; voltage-gated Ca 2ϩ channel ATRIAL FIBRILLATION (AF) is the most common clinical arrhythmia and is associated with significant mortality, primarily through stroke and heart failure (2, 3). There are many causes of AF and although patients generally show multiple predisposing risk factors, Ͼ70% of patients have some form of underlying structural heart disease (2, 3). Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained ...

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Section: H387mentioning

confidence: 81%

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Bond

Bryant

Watson

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…Studies overexpressing constitutively active I-1c reported improved contractility and resistance to cardiac overload and ischemia/reperfusion injury (15,16). On the other hand, Ppp1r1a KO mice had essentially normal cardiac function and were partially protected from acute and chronic catecholamine toxicity (12). To dissect the specific roles of I-1 in normal and diseased conditions, we generated 2 mouse models that allowed investigation of the effects of conditional cardiac-specific expression of I-1c/ I-1 S67A on a Ppp1r1a KO background.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, PKC-α phosphorylation at Ser67 attenuates I-1's inhibitory activity toward phosphatase-1, and this regulation of I-1 has been associated with depressed cardiac function in PKC-α transgenic mice (11). Notably, protein levels and PKA phosphorylation of I-1 were reduced in human failing hearts and were associated with decreased phosphorylation of PLB (12). Thus, I-1 downregulation likely participates in decreased SR Ca 2+ loading in failing myocytes.…”

Section: Introductionmentioning

confidence: 98%

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Wittköpper

Fabritz²,

Neef³

et al. 2010

J. Clin. Invest.

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Phosphatase inhibitor-1 (I-1) is a distal amplifier element of β-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyterestricted expression of I-1c (referred to herein as dTG I-1c mice) on an I-1-deficient background. Young adult dTG I-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyterestricted I-1c and reversed all abnormalities. Hearts from dTG I-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca 2+ sparks in isolated myocytes. Aged dTG I-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-α (I-1 S67A ). In conclusion, conditional expression of I-1c or I-1 S67A enhanced steady-state phosphorylation of 2 key Ca 2+ -regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure. IntroductionHeart failure is among the most frequent causes of morbidity and mortality worldwide and is, despite improved treatment options, associated with poor prognosis. Current treatment with angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, and beta blockers is suboptimal, with the 5-year survival rate being less than 50%. New drug principles targeting neurohumoral activation mechanisms, such as antagonists of endothelin receptors, TNF-α or IL-6, and statins, failed to improve survival in clinical studies. Thus, new approaches are needed, and an attractive one is to target the abnormal function of cardiomyocytes in failing hearts directly (as opposed to the more indirect affection by neurohumoral blockade).Two of the best studied alterations of failing myocyte function are (a) desensitization of the β-adrenergic signaling system (1, 2) and (b) alterations of intracellular Ca 2+ handling (3, 4). The latter include decreased diastolic sarcoplasmic reticulum (SR) Ca 2+ uptake via the SR Ca 2+ ATPase (SERCA2a) and relatively increased

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“…It has been proposed that differential anchoring of PP1 to various compartments can explain differences between RyR2 and PLB phosphorylation in HF. 19 Moreover, it was shown that SR-associated PP1 activity is increased 2.5-fold, suggesting that I-1 preferentially localize to the SR. 28 El-Armouche et al found a good correlation between PLB and I-1 phosphorylation in human HF supporting the notification of a causal relationship and arguing for preferential affection of PLB (at the free SR) compared with the RyR2 located at the junctional SR. 29 Taken together, CaMKII-induced phosphorylation effects via PLB may be ameliorated, whereas phosphorylation of the RyR2 may be excessive in human heart failure. Thus, inhibition of CaMKII rather exerts effects on SR Ca 2ϩ release in HF similar to our finding of an improved SR Ca 2ϩ leak in human atrial fibrillating myocardium.…”

Section: Camentioning

confidence: 99%

Inhibition of Elevated Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium

Sossalla

Fluschnik

Schotola

et al. 2010

Circulation Research

222

188

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Rationale: Heart failure (HF) is known to be associated with increased Ca 2؉ /calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.Objective: We sought to investigate detailed CaMKII␦ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility. Methods and Results:Expression analysis revealed that CaMKII␦, both cytosolic ␦ C and nuclear ␦ B splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca 2؉ loading. This was confirmed in isolated myocytes by a reduced SR Ca 2؉ spark frequency and hence SR Ca 2؉ leak, resulting in increased SR Ca 2؉ load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca 2؉ leak, was found to be markedly reduced in KN-93-treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.Conclusions: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKII␦ expression is increased. The mechanism proposed consists of a reduced SR Ca Key Words: Ca 2ϩ /calmodulin-dependent kinase II Ⅲ heart failure Ⅲ contractility Ⅲ calcium Ⅲ sarcoplasmic reticulum Ca 2ϩ leak Ⅲ ryanodine receptor H eart failure (HF) is accompanied by systolic and diastolic contractile dysfunction caused by abnormalities in intracellular Ca 2ϩ handling and structural remodeling. Several targets associated with the remodeling processes have been identified. The sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA) protein levels have been reported to be downregulated and paralleled by a reduced SR Ca 2ϩ uptake capacity in the human failing heart. [1][2][3] In contrast, the sarcolemmal Na ϩ /Ca 2ϩ exchanger protein expression and activity were found to be increased thereby even more effectively competing with the reduced SERCA activity for cytosolic Ca 2ϩ -removal. 3,4 The net effect is an impaired SR Ca 2ϩ loading, which leads to smaller intracellular Ca 2ϩ transients and elevated diastolic Ca 2ϩ levels in HF. 5 Thus, impaired contractility with reduced contractile force and diastolic dysfunction are well-accepted determinants in HF. 6 Intracellular Ca 2ϩ homeostasis of cardiac myocytes is also regulated by phosphorylation of several key Ca 2ϩ -handling proteins. An important regulatory kinase is the Ca 2ϩ /calmodulin-dependent protein kinase (CaMK)II. 7 It is a serine/ threonine protein kinase t...

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Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts

Abstract: The results suggest that the reduction in I-1 protein and phosphorylation in failing human hearts leads to increased phosphatase activity which in turn may result in reduced phosphorylation of cardiac proteins such as PLB.

Cited by 127 publications

References 25 publications

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Inhibition of Elevated Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium

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Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts

Abstract: The results suggest that the reduction in I-1 protein and phosphorylation in failing human hearts leads to increased phosphatase activity which in turn may result in reduced phosphorylation of cardiac proteins such as PLB.

Cited by 127 publications

References 25 publications

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Inhibition of Elevated Ca 2+ /Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium

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Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Inhibition of Elevated Ca ²⁺ /Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium