Selective activation of PI3Kα/Akt/GSK‐3β signalling and cardiac compensatory hypertrophy during recovery from heart failure

Braz, Julian C.; Gill, Robert M.; Corbly, Angela K.; Jones, Bonita D.; Jin, Najia; Vlahos, Chris J.; Wu, Qingyu; Shen, Wen

doi:10.1093/eurjhf/hfp094

Cited by 25 publications

(16 citation statements)

References 40 publications

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“…Both PKC 41 and PI3K 42 (particularly PI3K␣) 43 have been shown to regulate GSK3␤, which plays an important role in heart pump function. 44 However, Ang II infusion into hearts with conditional knockout of GSK3␤ induced biphasic changes (PϽ0.05; nϭ5) in ϩdP/dt max (Supplemental Figure IVA available online at http://hyper.ahajournals.org) that were not different (PϾ0.19, nϭ5) from changes induced by Ang II in wild-type littermate hearts.…”

Section: Resultsmentioning

confidence: 99%

“…PKC inhibition also reduced (PϽ0.01; nϭ7) the early-phase decrease in ϪdP/ dt min by Ϸ50% without affecting (Pϭ0.91; nϭ7) the latephase increase in ϪdP/dt min induced by Ang II (not shown). These results suggest that PKC plays a role in the negative and positive inotropic effects of Ang II.Both PKC 41 and PI3K 42 (particularly PI3K␣) 43 have been shown to regulate GSK3␤, which plays an important role in heart pump function. 44 However, Ang II infusion into hearts with conditional knockout of GSK3␤ induced biphasic changes (PϽ0.05; nϭ5) in ϩdP/dt max (Supplemental Figure IVA available online at http://hyper.ahajournals.org) that were not different (PϾ0.19, nϭ5) from changes induced by Ang II in wild-type littermate hearts.…”

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confidence: 83%

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Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

et al. 2010

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Abstract-Although angiotensin II (Ang II) plays an important role in heart disease associated with pump dysfunction, its direct effects on cardiac pump function remain controversial. We found that after Ang II infusion, the developed pressure and ϩdP/dt max in isolated Langendorff-perfused mouse hearts showed a complex temporal response, with a rapid transient decrease followed by an increase above baseline. Similar time-dependent changes in cell shortening and L-type Ca 2ϩ currents were observed in isolated ventricular myocytes. Previous studies have established that Ang II signaling involves phosphoinositide 3-kinases (PI3K). Dominant-negative inhibition of PI3K␣ in the myocardium selectively eliminated the rapid negative inotropic action of Ang II (inhibited by Ϸ90%), whereas the loss of PI3K␥ had no effect on the response to Ang II. Consistent with a link between PI3K␣ and protein kinase C (PKC), PKC inhibition (with GF 109203X) reduced the negative inotropic effects of Ang II by Ϸ50%. Although PI3K␣ and PKC activities are associated with glycogen synthase kinase-3␤ and NADPH oxidase, genetic ablation of either glycogen synthase kinase-3␤ or p47phox (an essential subunit of NOX2-NADPH oxidase) had no effect on the inotropic actions of Ang II. Our results establish that Ang II has complex temporal effects on contractility and L-type Ca 2ϩ channels in normal mouse myocardium, with the negative inotropic effects requiring PI3K␣ and PKC activities. Key Words: cardiac contraction Ⅲ Langendorff heart Ⅲ patch clamp Ⅲ glycogen synthase kinase-3␤ Ⅲ NADPH oxidase A ngiotensin II (Ang II) plays an important role in cardiovascular physiology and pathology. Circulating Ang II levels and the activity of the local cardiac renin-angiotensin system are increased in heart disease, including cardiac hypertrophy 1 and failure. 2 Chronic Ang II stimulation has been linked to cardiac remodeling (characterized by interstitial fibrosis, myocyte hypertrophy and death, and metabolism alterations), 3,4 which contributes to decreased mechanical function in heart disease. However, the acute actions of Ang II on cardiac function remain unclear and are controversial with positive, 5-8 negative, 9 or no 10,11 effects on cardiac contractility reported. Moreover, the signaling pathways mediating the inotropic effects of Ang II are not fully clear. The positive inotropic effects of Ang II have been previously linked to protein kinase C (PKC), 8 L-type Ca 2ϩ currents (I Ca,L ), 6 and ␤-Arrestin-2, 8 as well as secondary endothelin-1 release, 7 whereas negative inotropic effects have been associated with PKC 9,12 and p38 MAPK 9 activities. Ang II has also been shown to activate phosphoinositide 3-kinases (PI3K) in cardiac myocytes 13,14 and vascular smooth muscle. 15 Because the class IA PI3K, PI3K␣, enhances cardiac contraction strength 16 and I Ca,L 17,18 while the class IB PI3K, PI3K␥, decreases cardiac contractility, accelerates cAMP degradation, 19,20 and increases ␤-adrenergic receptor downregulation, 21 we examined the involvement of PI...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 83%

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

et al. 2010

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“…Furthermore, b-catenin signaling is required for regeneration of the soleus . Upregulation of both total muscle and myonuclear b-catenin occurs during exercise, load-induced muscle hypertrophy, and myocardial recovery after heart failure in vivo (Sakamoto et al 2004, Armstrong & Esser 2005, Braz et al 2009, and the Wnt/b-catenin pathway promotes insulin/IGF1-mediated reserve cell activation and myotube hypertrophy in vitro (Rochat et al 2004). The anti-atrophy effects of IGF1 in glucocorticoid-treated rats are via the AKT/GSK3b/b-catenin pathway (Schakman et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Gentile¹,

Nantermet²,

Vogel³

et al. 2009

Journal of Molecular Endocrinology

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Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5a-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.

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“…9) provides further support to the hypothesis that ouabain-induced hypertrophy may have some similarity to physiological hypertrophy. Since experimentally induced physiological hypertrophy through the activation of PI3KIA is indeed capable of antagonizing or reversing the consequences of pathological hypertrophy (2,3,18,22), more direct and rigorous testing of the potential benefits of digitalis treatment on induced pathological hypertrophy seems to be appropriate. Such studies remain to be done.…”

Section: Necessity Of Ncx1 For Ouabain's Positive Inotropic Effectmentioning

confidence: 99%

Different roles of the cardiac Na⁺/Ca²⁺-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy

Bai

Morgan

Giovannucci

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Previous studies have shown that digitalis drugs, acting as specific inhibitors of cardiac Na(+)/K(+)-ATPase, not only cause positive inotropic effects, but also activate cell signaling pathways that lead to cardiac myocyte hypertrophy. A major aim of this work was to assess the role of Na(+)/Ca(2+)-exchanger, NCX1, in the above two seemingly related drug effects. Using a mouse with ventricular-specific knockout (KO) of NCX1, ouabain-induced positive inotropy that was evident in isolated wild-type (Wt) hearts was clearly reduced in KO hearts. Ouabain also increased Ca(2+) transient amplitudes in Wt myocytes, but not in KO myocytes. Ouabain-induced activations of ERK 1/2 were noted in Wt myocytes, but not in KO myocytes; however, ouabain activated PI3K1A and Akt in both Wt and KO myocytes. Protein synthesis rate, as a measure of hypertrophy, was increased by ouabain in Wt and KO myocytes; these drug effects were prevented by a PI3K inhibitor but not by a MEK/ERK inhibitor. Hypertrophy caused by ET-1, but not that induced by ouabain, was accompanied by upregulation of BNP gene in Wt and KO myocytes. The findings indicate 1) the necessity of NCX1 for positive inotropic action of ouabain; 2) the irrelevance of NCX1 and ERK 1/2 activation to ouabain-induced hypertrophy; and 3) that hypertrophy caused by ouabain through the activation of PI3K1A/Akt pathway is likely to be beneficial to the heart.

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Selective activation of PI3Kα/Akt/GSK‐3β signalling and cardiac compensatory hypertrophy during recovery from heart failure

Cited by 25 publications

References 40 publications

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Different roles of the cardiac Na⁺/Ca²⁺-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy

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Selective activation of PI3Kα/Akt/GSK‐3β signalling and cardiac compensatory hypertrophy during recovery from heart failure

Cited by 25 publications

References 40 publications

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca 2+ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca 2+ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy

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Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca ²⁺ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Different roles of the cardiac Na⁺/Ca²⁺-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy