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

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.

Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation

“…This implies a long-term C16:1n7-directed remodeling processes in the myocardium, resulting in complete GLS normalization at the end of the study (Figure 3C,D), which cannot be seen with a supplementation of C18:1n9 (Supplementary Figure S1B). In accordance with our previous results, ISO application did not affect ejection fraction or fractional shortening (Figure 3B and Table 1), and had no effect on the other strain parameters (global radial peak strain and global circumferential peak strain) (Figure 3E,F) [5,8]. In addition, other echocardiographic parameters, such as diastolic left ventricular (LV) posterior wall thickness (LVPWd), diastolic LV internal diameter (LVIDd) and diastolic septum thickness (IVSd), as well as LV mass and heart weight, were not significantly different between both ISO-treated groups (Table 1).…”

“…To investigate the putative cardioprotective effects of C16:1n7 application in vivo, we used an established model of ISO-induced cardiac damage, described previously [ 5 , 6 , 7 , 8 ]. Briefly, 129 sv wt mice were daily orally supplemented with C16:1n7 or the vehicle [ 19 , 31 ].…”

“…To investigate the putative cardioprotective effects of C16:1n7 application in vivo, we used an established model of ISO-induced cardiac damage, described previously [5][6][7][8].…”

“…In addition, other echocardiographic parameters, such as diastolic left ventricular (LV) posterior wall thickness (LVPWd), diastolic LV internal diameter (LVIDd) and diastolic septum thickness (IVSd), as well as LV mass and heart weight, were not significantly different between both ISO-treated groups (Table 1). As changes in GLS in this mouse model were shown to be strongly associated with cardiac fibrosis [5,6,8], we next investigated the fibrotic changes studied in myocardial paraffin sections of the mice. As expected, ISO treatment led to the development of cardiac fibrosis (Figure 3G-I), and that process was significantly reduced by the C16:1n7 treatment, suggesting a putative anti-fibrotic action of C16:1n7.…”

“…Accelerated and continuous catecholamine load on cardiomyocytes causes increased cardiac contractility, as well as hypoxia, inflammation and cardiac apoptosis [ 4 ]. Thus, in our previous study, we used a model of catecholamine-induced cardiac damage to investigate the development of cardiac fibrosis, inflammation and apoptosis after isoproterenol (ISO) application to 129 sv mice [ 5 , 6 , 7 , 8 ].…”