Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Thiele, A; Luettges, K; Ritter, D; Beyhoff, N; Smeir, E; Grune, J; Steinhoff, JS; Schupp, M; Klopfleisch, R; Rothe, M; Wilck, N; Bartolomaeus, H; Migglautsch, AK; Breinbauer, R; Kershaw, EE; Grabner, GF; Zechner, R; Kintscher, U; Foryst-Ludwig, A.
Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage.
Cardiovasc Res. 2022; 118(11): 2488-2505. Doi: 10.1093/cvr/cvab182 [OPEN ACCESS]
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Co-authors Med Uni Graz

Grabner Gernot

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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.

Find related publications in this database (using NLM MeSH Indexing)

Adipose Tissue - metabolism

Adrenergic Agents - metabolism, pharmacology

Animals - administration & dosage

Catecholamines - metabolism

Heart Failure - administration & dosage

Lipase - genetics, metabolism

Lipolysis - administration & dosage

Male - administration & dosage

Mice - administration & dosage

Phenylurea Compounds - administration & dosage

Find related publications in this database (Keywords)

Adipose tissue

ATGL

Lipolysis

Catecholamine

Cardiac apoptosis

Heart failure

Atglistatin

Cardioprotection

Fibrosis

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