Journal
CARDIOVASCULAR RESEARCH
Volume 118, Issue 11, Pages 2488-2505Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvab182
Keywords
Adipose tissue; ATGL; Lipolysis; Catecholamine; Cardiac apoptosis; Heart failure; Atglistatin; Cardioprotection; Fibrosis
Categories
Funding
- DZHK (German Centre for Cardiovascular Research) [BER 5.4PR]
- DFG (Deutsche Forschungsgemeinschaft) [DFG-KI712/10-1]
- German Cardiac Society (DGK)
- German Heart Foundation (DHS)
- DFG [DFG-Schu 2546/5-1, 394046635-SFB 1365, DFG-KI 712/10-1]
- Berlin Institute of Health (BIH)
- Corona-Stiftung (Deutsches Stiftungszentrum, Essen, Germany)
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [852796]
- NIH [R01 DK090166]
- Foundation Charite
- DZHK
- Einstein Foundation/Foundation Charite [EVF-BIH-2018-440]
- [BER 5.4 PR]
- [BMBF/BfR1328-564m]
- European Research Council (ERC) [852796] Funding Source: European Research Council (ERC)
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The specific inhibitor of ATGL, Atglistatin, can alleviate catecholamine-induced cardiac damage by exerting anti-fibrotic and anti-apoptotic effects. These effects are likely mediated by non-cardiac tissues.
Aims Heart failure (HF) is characterized by an overactivation of beta-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, beta-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage. Methods and results Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion. Conclusion This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction.
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