Aims: Heart failure (HF) is characterised by an overactivation of β-adrenergic signalling that directly plays a role in impairment of myocardial function. Furthermore, β-adrenergic overactivation induces adipose tissue lipolysis, which might further worsen the introduction of HF. Lately, we shown that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in rodents. Within this study, we investigated the cardioprotective results of a brand new medicinal inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-caused cardiac damage.

Methods and results: Male 129/Sv rodents received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. 5 days just before ISO application, dental Atglistatin (2 mmol/kg diet) or control treatment was began. Two and twelve days following the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days following the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, that was considerably improved by the use of Atglistatin. No alterations in ejection fraction were observed. Further studies incorporated histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, adopted by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application caused subendocardial fibrosis along with a profound pro-apoptotic cardiac response, as shown utilizing an apoptosis-specific gene expression-array. Atglistatin treatment brought to some dramatic decrease in these pro-fibrotic and pro-apoptotic processes. Then we identified a particular group of essential fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acidity, palmitoleic acidity, and oleic acidity), which caused pro-apoptotic effects in cardiomyocytes. Atglistatin considerably blocked this adipocytic FA secretion.

Conclusion: This research demonstrates cardioprotective results of Atglistatin inside a mouse type of catecholamine-caused cardiac damage/disorder, involving anti-apoptotic and anti-fibrotic actions. Particularly, advantageous cardioprotective results of Atglistatin are most likely mediated by non-cardiac actions, supporting the notion that medicinal targeting of adipose tissue may provide an ideal way to deal with cardiac disorder.