The role of endothelial adipose triglyceride lipase (ecATGL) in heart failure with preserved ejection fraction (HFpEF)

Abstract Background and objectives Obesity is one of the major drivers of heart failure with preserved ejection fraction (HFpEF). Endothelial cells (EC) have an important barrier function including the control of lipid transport from the coronary circulation to the myocardium. This EC lipid transport involves, in addition to fast transcellular transport, processes of EC-lipogenesis and -lipolysis, and is likely involved in the development of cardiac lipid accumulation in obese phenotypes of HFpEF. In order to determine the role of EC lipid metabolism/transport in HFpEF, we generated mice with an EC-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, and subjected these mice to a hypertensive-obese two-hit HFpEF model. Methods and results Inducible endothelial-specific ATGL knockout (ecATGL-KO) mice were generated by crossbreeding Atgl fl/fl mice with Cdh5(PAC)-CreERT2 mice. For the induction of HFpEF, mice received a high fat diet (HFD, 60% kcal from fat) and L-NAME for 15 weeks, while control animals (Ctrl) received low fat diet (LFD, 10% kcal from fat) and water, as previously described. To analyse cardiac function, standard and speckle-tracking echocardiography were performed. After 15 weeks, Cre− littermates (wild type, wt) with HFpEF developed obesity and hypertension (body weight: wt-Ctrl: 33.8±2.5g vs. wt-HFpEF: 45.1±4.4g, p<0.0001; systolic blood pressure: wt-Ctrl: 99.9±3.7mmHg vs. wt-HFpEF: 135.5±5.6mmHg, p<0.0001), which did not significantly differ in ecATGL-KO mice. In parallel, wt-HFpEF mice developed established echocardiographic signs of HFpEF including diastolic dysfunction: E/é: (wt-Ctrl: −22.3±1.3 vs. wt-HFpEF: −45.2±3.8; p<0.0001), IVRT: (wt-Ctrl: 17.8±0.7ms vs. wt-HFpEF: 19.3±0.4ms; p= p<0.0001), and an impaired global longitudinal strain (GLS) (wt-Ctrl: −20.7±1.1% vs. wt-HFpEF 12.9±0.7%; p<0.0001). HFpEF parameters were significantly improved in ecATGL-KO mice after 15 weeks of HFD/L-NAME: (E/é: −28.9±2.8; p<0.0001 vs. wt-HFpEF; IVRT: 18.3±0.6; p<0.05 vs. wt-HFpEF; GLS: −19.1±1.7; p<0.0001 vs. wt-HFpEF). No changes in systolic function (EF) were observed. Electron microscopical investigations of cardiac (LV) tissue sections showed enhanced lipid droplet accumulation in coronary ECs of ecATGL-KO mice when compared to wt mice. Complementary in vitro experiments in HUVECs using an ATGL inhibitor or genetic deletion of Atgl using siRNA resulted in significant lipid droplet accumulation which did not affect EC survival and function. Conclusion This study demonstrates that the lack of ATGL in ECs attenuates the development of HFpEF. Enhanced lipid droplet accumulation in coronary ECs in the absence of ATGL may protect the myocardium from lipid overload, as seen in obese phenotypes of HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Einstein Foundation Berlin;DZHK (German Centre for Cardiovascular Research), partner site Berlin;DFG (Deutsche Forschungsgemeinschaft)