Interaction between A-kinase anchoring protein 5 and protein kinase A mediates CaMKII/HDAC signaling to inhibit cardiomyocyte hypertrophy after hypoxic reoxygenation

Zhang, Xu; Wang, Qiushu; Wang, Zhi; Zhang, Huabin; Zhu, Feng; Ma, Jie; Wang, Wei; Chen, Zhenzhen; Wang, Hegui

doi:10.1016/j.cellsig.2022.110569

Cited by 2 publications

(2 citation statements)

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“…As myocardial remodeling plays a crucial role in the development of heart failure and one of the critical characteristics of heart failure is disruptions in the metabolism of cardiac calcium, GLP-1RAs can prevent post-MI remodeling by influencing changes in the extracellular matrix and calcium handling [ 47 , 48 ]. Previous research showed that elevated intracellular calcium or disruption of its balance can activate CaMKII, causing arrhythmia, heart failure, cardiomyocyte apoptosis, contractile dysfunction, and hypertrophy [ 49 ]. Kareusser et al showed that CaMKII induces maladaptive cardiac remodeling and that its inhibition is a promising approach for attenuating the progression of heart failure [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Evidence that tirzepatide protects against diabetes-related cardiac damages

Taktaz,

Scisciola,

Fontanella

et al. 2024

Cardiovasc Diabetol

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Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. Methods A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. Results Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. Conclusion Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Evidence that tirzepatide protects against diabetes-related cardiac damages

Taktaz,

Scisciola,

Fontanella

et al. 2024

Cardiovasc Diabetol

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“…FOXM1 also drives TGF-β-induced endothelial to mesenchymal transition and, in cardiac endothelial cells, cooperates with the Brahma-related gene-1 ( Brg1 ) chromatin remodeler to trigger the angiotensin-converting enzymes pathological switch leading to angiotensin I-to-II conversion and cardiac hypertrophy [ 45 , 46 ]. Additionally, various studies report a cardioprotective role for A-kinase anchoring protein 5 ( Akap5 ) by regulating calcineurin, calcium/calmodulin-dependent protein kinase II, and β-adrenergic receptors in the heart [ [47] , [48] , [49] ]. Targeting the Hippo pathway, Foxm1 , and Akap5 has tremendous potential as a therapeutic strategy for cardiac fibrosis and hypertrophy, with implications for cardiovascular diseases like CRS.…”

Section: Discussionmentioning

confidence: 99%

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

Munguia-Galaviz,

Gutierrez-Mercado,

Miranda-Diaz

et al. 2024

Heliyon

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Interaction between A-kinase anchoring protein 5 and protein kinase A mediates CaMKII/HDAC signaling to inhibit cardiomyocyte hypertrophy after hypoxic reoxygenation

Cited by 2 publications

References 57 publications

Evidence that tirzepatide protects against diabetes-related cardiac damages

Evidence that tirzepatide protects against diabetes-related cardiac damages

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

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