Protein kinase TBK1/IKKε inhibitor Amlexanox improves cardiac function after acute myocardial infarction in rats

Mo, Changgan; Ha, Hui Riem; Tang, Xiuge; Lu, Xinxu; Wei, Yin; Luo, Dan; Zhou, Zhuodong

doi:10.23736/s0031-0808.20.03937-3

Cited by 4 publications

(10 citation statements)

References 18 publications

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“…However, ALX treatment failed to maintain proper cardiac function during CCS, while FSK treatment resulted in arrhythmias. Contrary to our findings, Mo et al (2020) reported that ALX improved cardiac function, but this was in acute myocardial infarction animal models and not during CCS or in an isoproterenol-induced cardiomyopathy model. Also, the ALX dosage they employed was 10 times more than what we used in this study.…”

Section: Discussioncontrasting

confidence: 99%

“…Similarly, FSK-AC/cAMP has been shown to adaptively modulate myocardial inflammatory responses (Lee et al, 2010;Shim et al, 2014). However, regarding ALX treatment, we found that it was not effective at decreasing myocardial inflammation, as Mo et al (2020) had reported. The discrepancies in these findings may be due to the differences in the cardiovascular disease model being investigated and the variation in ALX dosage employed.…”

Section: Discussionsupporting

confidence: 46%

“…It could be argued that ALX can inhibit IkB kinases and TANK-binding kinase 1 (TBK1) besides GRK5. Nonetheless, the inhibition of IkB kinases and TBK1 along with GRK5 by ALX, as demonstrated (Mo et al, 2020), still did not prevent the LVSD in PCH mice models. Also, further studies into determining the toxicity of ALX and FSK combined treatment and its impact on diastolic function and lung congestion during CCS will be required to fully ascertain their therapeutic and translational potentials.…”

Section: Discussionmentioning

confidence: 85%

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Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

Adzika

Hou

Adekunle

et al. 2021

Front. Cell Dev. Biol.

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Chronic catecholamine stress (CCS) induces the occurrence of cardiomyopathy—pathological cardiac hypertrophy (PCH), which is characterized by left ventricular systolic dysfunction (LVSD). Recently, mounting evidence has implicated myocardial inflammation in the exacerbation of pathological cardiac remodeling. However, there are currently no well-defined treatment interventions or regimes targeted at both the attenuation of maladaptive myocardial hypertrophy and inflammation during CCS to prevent PCH. G protein-coupled receptor kinase 5 (GRK5) and adenylyl cyclases (ACs)-cAMP mediates both cardiac and inflammatory responses. Also, GRK5 and ACs are implicated in stress-induced LVSD. Herein, we aimed at preventing PCH during CCS via modulating adaptive cardiac and inflammatory responses by inhibiting GRK5 and/or stimulating ACs. Isoproterenol-induced cardiomyopathy (ICM) was modeled using 0.5 mg/100 g/day isoproterenol injections for 40 days. Alterations in cardiac and inflammatory responses were assessed from the myocardia. Similarities in the immunogenicity of cardiac troponin I (cTnI) and lipopolysaccharide under CCS were assessed, and Amlexanox (35 μM/ml) and/or Forskolin (10 μM/ml) were then employed in vitro to modulate adaptive inflammatory responses by inhibiting GRK5 or activating ACs-cAMP, respectively. Subsequently, Amlexanox (2.5 mg/100 g/day) and/or Forskolin (0.5 mg/100 g/day) were then translated into in vivo during CCS to modulate adaptive cardiac and inflammatory responses. The effects of Amlexanox and Forskolin on regulating myocardial systolic functions and inflammatory responses during CCS were ascertained afterward. PCH mice had excessive myocardial hypertrophy, fibrosis, and aggravated LVSD, which were accompanied by massive CD68+ inflammatory cell infiltrations. In vitro, Forskolin-AC/cAMP was effective than Amlexanox-GRK5 at downregulating proinflammatory responses during stress; nonetheless, Amlexanox and Forskolin combination demonstrated the most efficacy in modulating adaptive inflammatory responses. Individually, the translated Amlexanox and Forskolin treatment interventions were ineffective at subduing the pathological remodeling and sustaining cardiac function during CCS. However, their combination was potent at preventing LVSD during CCS by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. The treatment intervention attained its potency mainly via Forskolin-ACs/cAMP-mediated modulation of cardiac and inflammatory responses, coupled with Amlexanox inhibition of GRK5 mediated maladaptive cascades. Taken together, our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for preventing the occurrence of pathological cardiac hypertrophy during chronic stress.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 85%

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Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

Adzika

Hou

Adekunle

et al. 2021

Front. Cell Dev. Biol.

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“…Also, AMLX and FSKN combine treatments were employed ( Figure 1A ). The dosages of AMLX and FSKN employed were based on their efficacies demonstrated in previous studies ( 2 , 11 ).…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, there are overwhelming numbers of studies demonstrating potential therapeutic intervention for acute myocardial infarction (AMI). Like AMI, ICM is characterized by exacerbated myocardial inflammation and LVSD ( 7 , 10 , 11 ). Hence, this study sought to explore if amlexanox (AMLX), which was recently demonstrated to aid in the recovery of cardiac function from AMI, could do the same in ICM models.…”

Section: Introductionmentioning

confidence: 99%

Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Adzika

Hou

Adekunle

et al. 2021

Front. Cardiovasc. Med.

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The increasing incidence of stress-induced cardiomyopathy is due to the complexities of our modern-day lives, which constantly elicit stress responses. Herein, we aimed to explore the therapeutic potential of Amlexanox and Forskolin in promoting the recovery from stress-induced cardiomyopathy. Isoproterenol-induced cardiomyopathy (ICM) models were made, and the following treatment interventions were administered: 5% v/v DMSO as a placebo, Amlexanox (2.5 mg/100 g/day) treatment, Forskolin (0.5 mg/100 g/day), and Amlexanox and Forskolin combination, at their respective aforementioned dosages. The effects of Amlexanox and Forskolin treatment on ICM models were assessed by eletrocardiography and echocardiography. Also, using histological analysis and ELISA, their impact on myocardial architecture and inflammation were ascertained. ICM mice had excessive myocardial fibrosis, hypertrophy, and aggravated LVSDs which were accompanied by massive CD86+ inflammatory cells infiltration. Amlexanox treatment attenuated the myocardial hypertrophy, fibrosis, and inflammation and also slightly improved systolic functions. Meanwhile, forskolin treatment resulted in arrhythmias but significantly enhanced the resolution of myocardial fibrosis and inflammation. Intriguingly, Amlexanox and Forskolin combination demonstrated the most potency at promoting the recovery of the ICM from LVSD by attenuating maladaptive myocardial hypertrophy, fibrosis, and inflammatory responses. Our findings highlight the Amlexanox and Forskolin combination as a potential therapeutic intervention for enhancing cardiac function recovery from stress-induced cardiomyopathy by promoting the resolution of maladaptive cardiac remodeling.

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Phosphorylation of AGO2 by TBK1 Promotes the Formation of Oncogenic miRISC in NSCLC

Zhao,

Cao,

et al. 2024

Advanced Science

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Non‐small‐cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank‐binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417‐AGO2), which promotes NSCLC progression by increasing the formation of microRNA‐induced silencing complex (miRISC). High levels of pS417‐AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417‐AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib‐resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1‐mediated pS417‐AGO2 and suggest potential therapeutic approaches for NSCLC.

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Protein kinase TBK1/IKKε inhibitor Amlexanox improves cardiac function after acute myocardial infarction in rats

Cited by 4 publications

References 18 publications

Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

Amlexanox and Forskolin Prevents Isoproterenol-Induced Cardiomyopathy by Subduing Cardiomyocyte Hypertrophy and Maladaptive Inflammatory Responses

Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

Phosphorylation of AGO2 by TBK1 Promotes the Formation of Oncogenic miRISC in NSCLC

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