Pharmacological inhibition of adipose tissue Adipose Triglyceride Lipase (ATGL) by Atglistatin prevents catecholamine-induced myocardial damage

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Item Type:	Article
Title:	Pharmacological inhibition of adipose tissue Adipose Triglyceride Lipase (ATGL) by Atglistatin prevents catecholamine-induced myocardial damage
Creators Name:	Thiele, A., Luettges, K., Ritter, D., Beyhoff, N., Smeir, E., Grune, J., Steinhoff, J.S., Schupp, M., Klopfleisch, R., Rothe, M., Wilck, N., Bartolomaeus, H., Migglautsch, A.K., Breinbauer, R., Kershaw, E.E., Grabner, G.F., Zechner, R., Kintscher, U. and Foryst-Ludwig, A.
Abstract:	AIMS: Heart failure (HF) is characterized by an overactivation of β-adrenergic signaling 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 analyzed 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 application of Atglistatin. No changes of 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. CONCLUSIONS: The present 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. TRANSLATIONAL PERSPECTIVE: The pharmacological inhibition of ATGL activity in adipose tissue improves heart function in a murine model of catecholamine-induced myocardial damage, via significant reduction of cardiac apoptosis and fibrosis. Our data strongly support the role of an adipose tissue-heart communication in the development of cardiac diseases, associated with increased sympathetic-tone. Atglistatin beneficial actions were only mild, when applied after the catecholamine-induced damage in a therapeutic manner. However, when given prior to the event in a preventive manner, Atglistatin strongly protected against cardiac damage. These data suggest that an Atglistatin-based therapy may be more suitable as a new pharmacological option in cardiovascular prevention.
Keywords:	Adipose Tissue, ATGL, Lipolysis, Catecholamine, Cardiac Apoptosis, Heart Failure, Atglistatin, Cardioprotection, Fibrosis, Animals, Mice
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Oxford University Press
Volume:	118
Number:	11
Page Range:	2488-2505
Date:	July 2022
Additional Information:	Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021.
Official Publication:	https://doi.org/10.1093/cvr/cvab182
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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