{"doi":"10.1093/cvr/cvab182","title":"Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage","abstract":"AIMS: Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-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.","journal":"Cardiovascular Research","year":2021,"id":159018,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670015,"name":"Katja Luettges","orcid":null,"position":1,"is_corresponding":false},{"id":669136,"name":"Daniel Ritter","orcid":"0000-0001-5465-5545","position":2,"is_corresponding":false},{"id":669137,"name":"Niklas Beyhoff","orcid":"0000-0001-9140-2336","position":3,"is_corresponding":false},{"id":669138,"name":"Elia Smeir","orcid":"0000-0003-1779-2844","position":4,"is_corresponding":false},{"id":642006,"name":"Jana Grune","orcid":"0000-0001-6209-7416","position":5,"is_corresponding":false},{"id":669139,"name":"Julia S. Steinhoff","orcid":"0000-0001-7508-6636","position":6,"is_corresponding":false},{"id":669140,"name":"Michael Schupp","orcid":"0000-0003-3720-1052","position":7,"is_corresponding":false},{"id":669141,"name":"Robert Klopfleisch","orcid":"0000-0002-6308-0568","position":8,"is_corresponding":false},{"id":669142,"name":"Michael Rothe","orcid":"0000-0002-4243-4582","position":9,"is_corresponding":false},{"id":628243,"name":"Nicola Wilck","orcid":"0000-0003-3189-5364","position":10,"is_corresponding":false},{"id":669143,"name":"Hendrik Bartolomaeus","orcid":"0000-0003-4288-3828","position":11,"is_corresponding":false},{"id":670016,"name":"Anna Katharina Migglautsch","orcid":null,"position":12,"is_corresponding":false},{"id":669144,"name":"Rolf Breinbauer","orcid":"0000-0001-6009-7359","position":13,"is_corresponding":false},{"id":235352,"name":"Erin E. 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