Abstract Body: Background:
Atherosclerosis and maladaptive cardiac remodeling are highly prevalent cardiovascular diseases that often coexist and account for high morbidity and mortality. Increasing evidence suggests that these processes are linked and share common pathophysiological mechanisms, such as dyslipidemia, inflammation, oxidative stress, and endothelial dysfunction. Group 2 innate lymphoid cells (ILC2) have emerged as important regulators of immune responses in cardiovascular disease. However, their role in early atherosclerosis and potential sex-related differences remains incompletely defined.
Hypothesis:
We hypothesized that ILC2 deficiency differently impacts early atherogenesis in male and female LDLR-deficient mice.
Methods:
Male and female LDLR ^-/- ILC2 ^-/- double knockout mice and LDLR ^-/- ILC2 ^+/+ were subjected to a 60% high-fat diet for 12 weeks. Atherosclerotic plaque burden at the aortic arch was quantified by en face aorta analysis. Cardiac structure and function were evaluated by echocardiography.
Results:
Two-way ANOVA showed a significant sex-genotype interaction for aortic arch plaque area (interaction p=0.014). In male mice, ILC2 deficiency increased plaque burden area compared to LDLR ^-/- ILC2 ^+/+ (2.56 ± 0.88%, n=5 vs 0.33 ± 0.08%, n=8), whereas no significant difference was observed in females (1.55 ± 0.2%, n=5 vs 2.06 ± 0.72%, n=5).
A significant sex-genotype interaction was also observed for circulating LDL cholesterol (interaction p=0.0009). In males, ILC2 deficiency was associated with increased LDL levels (80.88 ± 9.54 vs 158.6 ± 19.4 mg/dL), whereas no significant genotype effect was detected in females. Neither sex nor genotype alone had a significant effect on plaque burden. Although an increase in body weight was observed, echocardiographic parameters showed no signs of left ventricular remodeling at 12 weeks in both sexes.
Conclusion:
ILC2 deficiency affects early atherosclerosis in a sex-dependent manner, associated with a parallel change in blood levels of LDL cholesterol, without inducing overt cardiac remodeling at this stage. These findings identify ILC2 as a modulator of early plaque development and highlight the importance of biological sex in immune-mediated cardiovascular diseases.