The role of PP5 and PP2C in cardiac health and disease

Neumann, Joachim; Boknı́k, Peter; Kirchhefer, Uwe; Gergs, Ulrich

doi:10.1016/j.cellsig.2021.110035

Cited by 15 publications

(10 citation statements)

References 310 publications

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“…This suggests that the local PP5 expression may be regulated by a circulating inflammatory signal other than TNF-α. Although PP5 expression is known to be regulated by several intracellular signals [16,17], the extracellular signals that stimulate these pathways to PP5 expression and activity require further investigation. Since both the upregulation of PP5 expression and the accompanying LV diastolic dysfunction are not mediated by TNF-α, our results suggest that LV diastolic dysfunction may, at least in part, result from increased expression of PP5, which increases cardiomyocyte stiffness by decreasing the net phosphorylation level of the N2-Bus stretch element of titin, whereas disruption of the NO-sGC-cGMP pathway is likely less important.…”

Section: Discussionmentioning

confidence: 99%

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Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Manilall

Mokotedi

Gunter

et al. 2022

BMC Cardiovasc Disord

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Background Titin phosphorylation contributes to left ventricular (LV) diastolic dysfunction. The independent effects of inflammation on the molecular pathways that regulate titin phosphorylation are unclear. Methods We investigated the effects of collagen-induced inflammation and subsequent tumor necrosis factor-α (TNF-α) inhibition on mRNA expression of genes involved in regulating titin phosphorylation in 70 Sprague-Dawley rats. LV diastolic function was assessed with echocardiography. Circulating inflammatory markers were quantified by enzyme-linked immunosorbent assay and relative LV gene expression was assessed by Taqman® polymerase chain reaction. Differences in normally distributed variables between the groups were determined by two-way analysis of variance (ANOVA), followed by Tukey post-hoc tests. For non-normally distributed variables, group differences were determined by Kruskal–Wallis tests. Results Collagen inoculation increased LV relative mRNA expression of vascular cell adhesion molecule 1 (VCAM1), pentraxin 3 (PTX3), and inducible nitric oxide synthase (iNOS) compared to controls, indicating local microvascular inflammation. Collagen inoculation decreased soluble guanylate cyclase alpha-2 (sGCα2) and soluble guanylate cyclase beta-2 (sGCβ2) expression, suggesting downregulation of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling. Inhibiting TNF-α prevented collagen-induced changes in VCAM1, iNOS, sGCα2 and sGCβ2 expression. Collagen inoculation increased protein phosphatase 5 (PP5) expression. Like LV diastolic dysfunction, increased PP5 expression was not prevented by TNF-α inhibition. Conclusion Inflammation-induced LV diastolic dysfunction may be mediated by a TNF-α-independent increase in PP5 expression and dephosphorylation of the N2-Bus stretch element of titin, rather than by TNF-α-induced downregulation of NO-sGC-cGMP pathway-dependent titin phosphorylation. The steady rise in number of patients with inflammation-induced diastolic dysfunction, coupled with low success rates of current therapies warrants a better understanding of the systemic signals and molecular pathways responsible for decreased titin phosphorylation in development of LV diastolic dysfunction. The therapeutic potential of inhibiting PP5 upregulation in LV diastolic dysfunction requires investigation.

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Section: Discussionmentioning

confidence: 99%

“…It was suggested that "pathological triggers" may activate PP5 in heart disease [16]. Although the proximal intracellular signaling molecules that activate PP5 have been reported [16,17], it is unknown whether systemic inflammation affects PP5 activity or expression.…”

Section: Introductionmentioning

confidence: 99%

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Manilall

Mokotedi

Gunter

et al. 2022

BMC Cardiovasc Disord

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“…Data were treated as in most our previous studies (e.g., Gergs et al 2019a ; Neumann et al 2021a , b ). Shown are means ± standard error of the mean.…”

Section: Methodsmentioning

confidence: 99%

Effects of omecamtiv mecarbil and mavacamten in isolated human atrium

Abella

Höhm

Hofmann

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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Heart failure is a syndrome that can result from impaired heart muscle contractions like in dilative cardiomyopathy but also from hypertrophic obstructive cardiomyopathy (HOCOM). A pharmacological therapy might lie in Ca2+-sensitizing or Ca2+-desensitizing drugs, respectively. Such drugs are thought to be omecamtiv mecarbil (OME) and mavacamten (MYK-461), respectively. Their function in contracting human muscle is not fully understood and was the focus of the present study. OME from 1 nM to 10 µM cumulatively applied failed to raise force of contraction in human right atrial preparations strips (HAP) or mouse left atrial preparations (LA). However, OME prolonged time to peak tension and time of relaxation in HAP and LA but did not alter the beating rate in right atrial preparations from mice (RA). In contrast, MYK-461 (10 nM to 10 µM) reduced concentration- and time-dependently force of contraction in HAP and LA. MYK-461 (10 µM) did not affect the beating rate in RA. In summary, the present data failed to detect an increase in force of contraction for OME, in human and mouse atrium. In contrast, a Ca2+ desensitizer studied for comparison was able to reduce force of contraction in HAP and LA. We conclude that putative beneficial effects of OME in dilated cardiomyopathy cannot be explained by positive inotropic effects in the HAP, whereas beneficial functional effects of MYK-461 in HOCOM can be explained by negative inotropic effects in HAP.

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“…There is evidence that binding of sarcolemmal receptors to phosphatase by scaffolding complexes may occur but this matter is subject of active ongoing research (Neumann et al 2021.…”

Section: Introductionmentioning

confidence: 99%

Cantharidin and sodium fluoride attenuate the negative inotropic effects of carbachol in the isolated human atrium

Schwarz

Hofmann

Gergs

et al. 2023

Preprint

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Introduction: Carbachol, an agonist at muscarinic receptors, exerts negative inotropic effects in human atrium. Carbachol can activate protein phosphatases (PP1 or PP2A). We hypothesized that cantharidin or sodium fluoride, inhibitors of PP1 and PP2A, might attenuate negative inotropic effects of carbachol. Methods: During bypass-surgery trabeculae carneae human atrial preparations (HAP) were obtained. These trabeculae were mounted in organ baths and electrically stimulated (1 Hz). Force of contraction was measured under isometric conditions. For comparison, we studied isolated electrically stimulated left atrial preparations (LA) from mice. Results: 100 µM cantharidin and 3 mM sodium fluoride increased force of contraction in LA (n = 5-8, p < 0.05) by 113 % ± 24.5 % and by 100 % ± 38.2 % and in HAP (n = 13-15, p < 0.05 ) by 625 % ± 169 % and by 196 % ± 23.5 %, respectively. Carbachol 1 µM alone exerted a rapid transient maximum negative inotropic in LA (n = 6) and HAP (n = 14) to 46.9 % ± 3.63 % and 19.4 % ± 3.74 %, respectively (p < 0.05). These negative inotropic effects were smaller in LA (n = 4-6) and HAP (n = 9-12) pretreated with 100 µM cantharidin and amounted to 58.0 % ± 2.27 % and 59.2 % ± 6.19 % or 3 mM sodium fluoride to 63.7 % ± 9.84 % and 46.3 % ± 5.69 %, (p<0.05). Conclusion: We suggest that carbachol, in part, exerts a negative inotropic effect in the human atrium by putatively stimulating the enzymatic activity of PP1 and/or PP2A.

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The role of PP5 and PP2C in cardiac health and disease

Cited by 15 publications

References 310 publications

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

Effects of omecamtiv mecarbil and mavacamten in isolated human atrium

Cantharidin and sodium fluoride attenuate the negative inotropic effects of carbachol in the isolated human atrium

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