Publication Database

Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage (2022)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Thiele, Arne

Luettges, Katja

Ritter, Daniel

Beyhoff, Niklas

Smeir, Elia

Grune, Jana

Steinhoff, Julia S.

Schupp, Michael

Klopfleisch, Robert (WE 12)

Rothe, Michael

Wilck, Nicola

Bartolomaeus, Hendrik

Migglautsch, Anna K.

Breinbauer, Rolf

Kershaw, Erin E.

Grabner, Gernot F.

Zechner, Rudolf

Kintscher, Ulrich

Foryst-Ludwig, Anna

Quelle

Cardiovascular research : journal of the European Society of Cardiology

Bandzählung: 118

Heftzählung: 11

Seiten: 2488 – 2505

ISSN: 0008-6363

Sprache

Englisch

Verweise

URL (Volltext): https://academic.oup.com/cardiovascres/article/118/11/2488/6290710

DOI: 10.1093/cvr/cvab182

Pubmed: 34061169

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.