AMP Activated Protein Kinase-α2 Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Zhang, Ping; Hu, Xinli; Xu, Xin; Fassett, John; Zhu, Guangshuo; Viollet, Benoı̂t; Xu, Wayne; Wiczer, Brian M.; Bernlohr, David A.; Bache, Robert J.; Chen, Yingjie

doi:10.1161/hypertensionaha.108.114702

Cited by 169 publications

(171 citation statements)

References 29 publications

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“…AMPK␣1 (49) or AMPK␣2 (50) or that express a dominant negative form of AMPK␣2 expressed from MCK or ␣-MHC promoters (51,52). However, AMPK␣2-KO mice are reported to exhibit a modest increase in left ventricular hypertrophy compared with wild-type in response to pressure overload (53). At least two explanations can account for the discrepancy between the subtle phenotype seen with the AMPK stains and the pronounced cardiac phenotype in the LKB1-KO mouse line that is reported here.…”

Section: Discussionmentioning

confidence: 99%

Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

Ikeda

Sato

Pimentel

et al. 2009

Journal of Biological Chemistry

145

130

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LKB1 encodes a serine/threonine kinase, which functions upstream of the AMP-activated protein kinase (AMPK) superfamily. To clarify the role of LKB1 in heart, we generated and characterized cardiac myocyte-specific LKB1 knock-out (KO) mice using ␣-myosin heavy chain-Cre deletor strain. LKB1-KO mice displayed biatrial enlargement with atrial fibrillation and cardiac dysfunction at 4 weeks of age. Left ventricular hypertrophy was observed in LKB1-KO mice at 12 weeks but not 4 weeks of age. Collagen I and III mRNA expression was elevated in atria at 4 weeks, and atrial fibrosis was seen at 12 weeks. LKB1-KO mice displayed cardiac dysfunction and atrial fibrillation and died within 6 months of age. Indicative of a prohypertrophic environment, the phosphorylation of AMPK and eEF2 was reduced, whereas mammalian target of rapamycin (mTOR) phosphorylation and p70S6 kinase phosphorylation were increased in both the atria and ventricles of LKB1-deficient mice. Consistent with vascular endothelial growth factor mRNA and protein levels being significantly reduced in LKB1-KO mice, these mice also exhibited a reduction in capillary density of both atria and ventricles. In cultured cardiac myocytes, LKB1 silencing induced hypertrophy, which was ameliorated by the expression of a constitutively active form AMPK or by treatment with the inhibitor of mTOR, rapamycin. These findings indicate that LKB1 signaling in cardiac myocytes is essential for normal development of the atria and ventricles. Cardiac hypertrophy and dysfunction in LKB1-deficient hearts are associated with alterations in AMPK and mTOR/ p70S6 kinase/eEF2 signaling and with a reduction in vascular endothelial growth factor expression and vessel rarefaction.LKB1 is a ubiquitously expressed serine/threonine kinase that functions upstream of the 13 members of the AMP-activated protein kinase (AMPK) 5 superfamily (1). Analyses of LKB1-knock-out (KO) mouse models reveal that this kinase controls the physiological functions of many tissues. For instance, whole body LKB1-KO mice display embryonic lethality due to defects in the development of the neural tube, mesenchymal cell death, and abnormal vascular development (2). In addition, tissue-specific ablation of LKB1 has revealed that LKB1 also plays a major role in the regulation of cellular metabolism, likely via its role as an upstream AMPK-kinase (3-5). Although the role of LKB1 in the regulation of metabolic processes is under intense investigation, LKB1 also functions as a tumor suppressor, and its loss leads to the development of Peutz-Jeghers syndrome (6, 7). Importantly, at a cellular level LKB1 controls proliferation and cell polarity (8), which contributes to the tumor-inhibitory actions of LKB1.Consistent with the role of LKB1 in cell growth control, our recent work has shown that increased cardiac myocyte LKB1 activity contributes to the inhibition of protein synthesis involved in cardiac hypertrophy (9). Conversely, reduced LKB1 expression and/or activity has been shown in the hypertrophied hearts of various ...

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Section: Discussionmentioning

confidence: 99%

Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

Ikeda

Sato

Pimentel

et al. 2009

Journal of Biological Chemistry

145

130

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“…In this study, we investigated the protective effect of CYP2J2 in Ang II‐infused mice and the effect of exogenous EETs on PE‐induced model of cellular hypertrophy. AMPKα2 deficiency exacerbates pressure overload‐induced left ventricular hypertrophy and cardiac dysfunction in mice (Zhang et al ., 2008) and we demonstrated that exogenous EET treatment activates AMPK in mouse heart tissue (Ma et al ., 2013). Thus, it was reasonable to postulate that AMPKα2 activation might mediate the protective effects of CYP2J2 overexpression or EETs against the development of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 86%

“…In addition, the activation of AMPK protects against the development of cardiac hypertrophy or cardiac contractile dysfunction through mechanisms including (p‐70S6K Thr389 )‐(p‐elf4e Ser209 )‐(p‐4EBP1 Thr46 )‐mediated protein synthesis pathway or associated with AMPK‐mTORC1‐ULK1‐mediated autophagy (Zhang et al ., 2008; Turdi et al ., 2011; Guo & Ren, 2012). However, whether EET‐mediated protection against the development of cardiac hypertrophy occurs via the activation of AMPK needs to be further investigated.…”

Section: Introductionmentioning

confidence: 99%

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

et al. 2016

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SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

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“…The unintentional inhibition of AMPK is thought to activate energyconsuming processes, including protein translation and lipid biosynthesis, which can deplete ATP. Given the tremendous energetic demands of the contracting cardiomyocyte, the improper activation of ATP-consuming processes can be highly toxic (Dyck and Lopaschuk, 2006;Zhang et al, 2008).…”

Section: Sarcoplasmic Reticulum and Mitochondrial Homeostasismentioning

confidence: 99%

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

Shim

2018

Biophysical Journal

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Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation-contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

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AMP Activated Protein Kinase-α2 Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Cited by 169 publications

References 29 publications

Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

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