Investigating the Role of ILC2s in the Development of Atherosclerosis and HFpEF

Abstract

Atherosclerosis and heart failure with preserved ejection fraction (HFpEF) are highly prevalent cardiovascular conditions that often coexist, contributing to significant morbidity and mortality. Despite its clinical relevance, the driving pathological mechanisms inducing HFpEF remain incompletely understood. Type 2 innate lymphoid cells (ILC2s) have emerged as key modulators of tissue repair and inflammation, yet their role in cardiovascular disease remains poorly defined. In this study, we aimed to investigate the contribution of ILC2s to the development of atherosclerosis and HFpEF using double knockout (DKO) mice deficient in low-density lipoprotein receptor (LDLR) and ILC2 signaling. Mice were subjected to a high-fat diet and treated water containing L-NAME and salt to establish a three-hit model combining obesity, hypertension, and dyslipidemia. Our results demonstrated a successful induction of atherosclerotic lesions, which were more pronounced in female mice; however, the HFpEF phenotype was not achieved, as diastolic functions remained preserved. Consequently, the specific contribution of ILC2s to HFpEF pathogenesis could not be fully elucidated. In conclusion, while our model effectively reproduced diet- and sex-dependent atherosclerosis, further optimization is required to establish a reproducible HFpEF phenotype.