Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation

Abstract

Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1α, β, and γ in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of β-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression. Using western blot analysis, we found greater abundance of PP1 isoforms α and γ but unaltered PP1β levels in left ventricular myocardial tissues from HF patients as compared to non-failing controls. However, expression of all three PP1 isoforms was higher in atrial appendages from patients with AF compared to patients with sinus rhythm. Moreover, we found that in human failing ventricles, beta-blocker therapy was associated with lower PP1α abundance and activity, as indicated by higher phosphorylation of the PP1α-specific substrate eIF2α. Greater eIF2α phosphorylation is a known repressor of protein translation, and accordingly, we found lower levels of the endoplasmic reticulum (ER) stress marker Grp78 in the very same samples. We propose that isoform-specific targeting of PP1α activity may be a novel and innovative therapeutic strategy for the treatment of human cardiac diseases by reducing ER stress conditions.

Activation of endogenous protein phosphatase 1 enhances the calcium sensitivity of the ryanodine receptor type 2 in murine ventricular cardiomyocytes

“…Interestingly, β‐adrenergic receptor blocking therapy was associated with lower PP‐1 abundance and activity in human failing ventricles, suggesting phosphatases rather than kinases as possible targets for the treatment of some human cardiac diseases (Meyer‐Roxlau et al . ). Furthermore, inhibition of RyR2 phosphorylation at S2808 was shown to exacerbate cardiac dysfunction in a model of Ca 2+ ‐dependent cardiomyopathy, suggesting a role for de‐phosphorylation of RyR2 in pathophysiological Ca 2+ handling (Liu et al .…”

Dietary ω-3 fatty acids reduced atrial fibrillation vulnerability via attenuating myocardial endoplasmic reticulum stress and inflammation in a canine model of atrial fibrillation

“…In line with above hypothesis, we observed reduced AF vulnerability and decreased AF duration post fish oil treatment, thus fish oil could attenuate electrical remodeling in this RAP-induced AF model. during AF [21][22][23][24]. ERS marker protein such as glucose-regulated protein78 (GRP78) was significantly increased in the tachypacing induced AF model and atrial myocardium obtained from AF patients [23,24].…”

“…during AF [21][22][23][24]. ERS marker protein such as glucose-regulated protein78 (GRP78) was significantly increased in the tachypacing induced AF model and atrial myocardium obtained from AF patients [23,24]. UPR effectors like protein kinase R-like ER kinase (PERK) could destabilize voltage-gated cardiac Na + channel α-subunit (SCN5A) and Kv4.3 channel expression, which were important mediators of electric remodeling 22 .…”

Abcb1a and Abcb1b genes function differentially in blood–testis barrier dynamics in the rat

“… 32 Moreover, since TJ is an actin-based cell junction type, a correspondence between ZO-1 alpha + and F-actin may indicate the influence of the spatial organizaiton of subsurface actin on alpha + or alpha − -involved TJ assembly/disassembly. 32 In human, the isoform-specific activities of protein phosphatase 1 (PP1) in heart failure and atrial fibrillation have been reported, 33 results proposed that isoform-specific targeting of PP1 α activity might be an innovative stragegy for human cardiac diseases but not PP1 β or PP1 γ . 33 …”

“… 32 In human, the isoform-specific activities of protein phosphatase 1 (PP1) in heart failure and atrial fibrillation have been reported, 33 results proposed that isoform-specific targeting of PP1 α activity might be an innovative stragegy for human cardiac diseases but not PP1 β or PP1 γ . 33 …”