Abstract 2144: Smooth Muscle Cell Specific Beclin-1 Deficiency Promotes Aging-accelerated Aortic Stiffness In Mice

Background and Objective: Aortic stiffness, a hallmark of aging, is a significant riskfactor for cardiovascular diseases like hypertension and atherosclerosis. Vascularsmooth muscle cells (SMCs) play a crucial role in maintaining aortic structural integrity,and increased SMC stiffness contributes to age-accelerated aortic stiffness.Autophagy, a self-regulatory cellular process, declines with aging, predisposingindividuals to age-related diseases. Reduced levels of Beclin-1, a key autophagyinduction gene, have been observed in aging-associated diseases. However, thecontribution of SMC-derived Beclin-1 in aortic stiffness progression remains unknown.This study examined the contribution of SMC-derived Beclin-1 to aortic stiffnessdevelopment in mice. Methods and Results: Ultrasound measurements revealed increased aortic stiffnessin 60-week-old aged mice, characterized by elevated pulse-wave velocity (PWV) andreduced aortic distensibility and radial strain compared to 8-week-old young mice.Western blot and immunohistochemistry analyses showed a decline of aortic Beclin-1in the SMC-rich aortic medial layer of aged mice. To investigate the role of SMC-Beclin-1 in aortic stiffness, mice with inducible SMC-Beclin-1 deletion were generated bybreeding Acta2-CreERT2 hemizygous mice with Beclin-1 floxed mice. Baselinemeasurements at 8 weeks showed no PWV difference between Beclin-1 x Acta2-CreERT2 (Cre+) and non-Cre littermates (Cre-). However, following tamoxifen-induced Cre recombination, SMC-Beclin-1 deficiency significantly accelerated PWVby 18 weeks (Cre-: 2.4 ± 0.1 vs Cre+: 4.1 ± 0.2 m/s; P<0.001), accompanied byreduced aortic distensibility (Cre-:115.4 ± 3.2 vs Cre+: 93.1 ± 3.4; P<0.001) and radialstrain(Cre-:20.3 ± 0.7 vs Cre+:15.8 ± 0.7; P<0.001). Histological analyses indicatedthat Beclin-1 deficiency increased collagen deposition in aortic media and adventitia.RNA Sequencing and Western blot analyses identified extracellular matrix regulatingGalectin-3 and S100A4 as novel targets of Beclin-1, selectively upregulated in SMC-Beclin-1 deficient aorta. Conclusion: These findings suggest that SMC-derived Beclin-1 plays a critical rolein suppressing aging-accelerated aortic stiffness in mice.