Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways

Clemente, Carolina F.M.Z.; Xavier‐Neto, José; Costa, Ana Paula Dalla; Consonni, Sílvio Roberto; Antunes, João Eustáquio; Rocco, Silvana A.; Pereira, Michelle B. M.; Judice, Carla C.; Strauss, Bryan E.; Joazeiro, Paulo Pinto; Matos‐Souza, José R.; Franchini, Kleber G.

doi:10.1016/j.yjmcc.2011.10.015

Cited by 56 publications

(51 citation statements)

References 40 publications

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“…In addition, we applied FAK inhibitor (PF‐562271) in cADAM23‐KO mice to further confirm the role of FAK/AKT signaling pathway in ADAM23‐mediated regulation of cardiac hypertrophy. Of note, several previous researches supported our findings: FAK deletion attenuates load‐induced hypertrophy,23, 27 while increased FAK activity causes cardiac hypertrophy 22. Importantly, by using the same FAK inhibitor as used in our study, Clemente et al demonstrated that FAK activation causes cardiac concentric hypertrophy by activating the AKT and mTOR pathways 22.…”

Section: Discussionsupporting

confidence: 87%

“…Of note, several previous researches supported our findings: FAK deletion attenuates load‐induced hypertrophy,23, 27 while increased FAK activity causes cardiac hypertrophy 22. Importantly, by using the same FAK inhibitor as used in our study, Clemente et al demonstrated that FAK activation causes cardiac concentric hypertrophy by activating the AKT and mTOR pathways 22. However, some studies also reported that deletion of FAK in cardiomyocytes promotes eccentric cardiac hypertrophy in mice 28, 29.…”

Section: Discussionsupporting

confidence: 86%

“…Unexpectedly, MAPK activities were affected by neither ADAM23 deficiency nor overexpression in heart tissue (Figure 5A). According to previous studies, the FAK/AKT signaling cascade is another signaling pathway which plays an important role in the process of cardiac hypertrophy 22, 23. On the contrary, we found that FAK phosphorylation levels and its downstream molecules AKT/GSK3β/mTOR were significantly elevated in the cADAM23‐KO group and blunted in the ADAM23‐TG group in AB‐induced hypertrophy compared with the controls in vivo (Figure 5B).…”

Section: Resultssupporting

confidence: 61%

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ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

Xiang

Luo

et al. 2018

JAHA

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BackgroundCardiac hypertrophy has been recognized as an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality. A disintegrin and metalloprotease 23 (ADAM23), a member of ADAM family, is involved in cancer and neuronal differentiation. Although ADAM23 is expressed in the heart, the role of ADAM23 in the heart and in cardiac diseases remains unknown.Methods and ResultsWe observed that ADAM23 expression is decreased in both failing human hearts and hypertrophic mice hearts. Cardiac‐specific conditional ADAM23‐knockout mice significantly exhibited exacerbated cardiac hypertrophy, fibrosis, and dysfunction, whereas transgenic mice overexpressing ADAM23 in the heart exhibited reduced cardiac hypertrophy in response to pressure overload. Consistent results were also observed in angiotensin II‐induced neonatal rat cardiomyocyte hypertrophy. Mechanistically, ADAM23 exerts anti‐hypertrophic effects by specifically targeting the focal adhesion kinase‐protein kinase B (FAK‐AKT) signaling cascade. Focal adhesion kinase inactivation by inhibitor (PF‐562271) greatly reversed the detrimental effects in ADAM23‐knockout mice subjected to aortic banding.ConclusionAltogether, we identified ADAM23 as a negative regulator of cardiac hypertrophy through inhibiting focal adhesion kinase‐protein kinase B signaling pathway, which could be a promising therapeutic target for this malady.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 86%

Section: Resultssupporting

confidence: 61%

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ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

Xiang

Luo

et al. 2018

JAHA

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“…Focal adhesion kinase (FAK) is a mediator of the hypertrophic growth and survival of cardiomyocytes during mechanical stress [16][17][18][19] . However, the regulation of FAK in this particular cell type remains unclear.…”

mentioning

confidence: 99%

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Pereira¹,

Santos²,

Gonçalves³

et al. 2014

Nat Commun

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Focal adhesion kinase (FAK) contributes to cellular homeostasis under stress conditions. Here we show that aB-crystallin interacts with and confers protection to FAK against calpainmediated proteolysis in cardiomyocytes. A hydrophobic patch mapped between helices 1 and 4 of the FAK FAT domain was found to bind to the b4-b8 groove of aB-crystallin. Such an interaction requires FAK tyrosine 925 and is enhanced following its phosphorylation by Src, which occurs upon FAK stimulation. aB-crystallin silencing results in calpain-dependent FAK depletion and in the increased apoptosis of cardiomyocytes in response to mechanical stress. FAK overexpression protects cardiomyocytes depleted of aB-crystallin against the stretch-induced apoptosis. Consistently, load-induced apoptosis is blunted in the hearts from cardiac-specific FAK transgenic mice transiently depleted of aB-crystallin by RNA interference. These studies define a role for aB-crystallin in controlling FAK function and cardiomyocyte survival through the prevention of calpain-mediated degradation of FAK.

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“…ECM accumulation is common in multiple cardiovascular diseases, leading to heart failure. Focal adhesion kinase activation could be important for the adaptive response to increase in cardiac afterload by controlling the activity of PI3K/AKT/mTOR pathway 23. AMP‐activated protein kinase (AMPK) is activated when intracellular ATP production decreases.…”

Section: Resultsmentioning

confidence: 99%

Integrative analysis of competing endogenous RNA networks reveals the functional lncRNAs in heart failure

Fan

Gao

Chen

et al. 2018

J Cellular Molecular Medi

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Heart failure has become one of the top causes of death worldwide. It is increasing evidence that lncRNAs play important roles in the pathology processes of multiple cardiovascular diseases. Additionally, lncRNAs can function as ceRNAs by sponging miRNAs to affect the expression level of mRNAs, implicating in numerous biological processes. However, the functional roles and regulatory mechanisms of lncRNAs in heart failure are still unclear. In our study, we constructed a heart failure‐related lncRNA‐mRNA network by integrating probe re‐annotation pipeline and miRNA‐target interactions. Firstly, some lncRNAs that had the central topological features were found in the heart failure‐related lncRNA‐mRNA network. Then, the lncRNA‐associated functional modules were identified from the network, using bidirectional hierarchical clustering. Some lncRNAs that involved in modules were demonstrated to be enriched in many heart failure‐related pathways. To investigate the role of lncRNA‐associated ceRNA crosstalks in certain disease or physiological status, we further identified the lncRNA‐associated dysregulated ceRNA interactions. And we also performed a random walk algorithm to identify more heart failure‐related lncRNAs. All these lncRNAs were verified to show a strong diagnosis power for heart failure. These results will help us to understand the mechanism of lncRNAs in heart failure and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets.

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Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways

Cited by 56 publications

References 40 publications

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Integrative analysis of competing endogenous RNA networks reveals the functional lncRNAs in heart failure

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