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

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.