Abstract Body: Introduction: Aortic stiffness, a hallmark of aging, is a significant risk factor for cardiovascular diseases like hypertension and atherosclerosis. In our preliminary studies, smooth muscle cell-specific Beclin-1 deficiency in mice accelerated aortic stiffness which is associated with a significant increase in Galectin-3. An increased level of Galectin-3, a galactoside-binding lectin, is shown to be associated with arterial stiffness in cardiovascular patients. In this study, we aim to investigate the effect of galectin inhibition on aortic stiffness development in SMC-Beclin-1 deficient mice.
Methods and Results: Tamoxifen-inducible SMC-Beclin-1 deficient mice were generated by breeding Acta2-CreERT2 hemizygous mice with Beclin-1 floxed mice. Male SMC Beclin-1 wild type (Cre-) or deficient (Cre+) mice (n=7-8/group) were administered with either vehicle (VC) or galectin inhibitor (GI-100 mg/kg/day) in drinking water for 7 weeks. Post 8 weeks of tamoxifen injection, as measured by ultrasound, SMC-Beclin-1 deficiency (Cre+) in mice spontaneously accelerated aortic stiffness as evidenced by a significant increase in aortic pulse wave velocity (PWV- Cre-: 2.2±0.05 vs Cre+: 3.5±0.2 m/s; P<0.001) with decreased radial strain and distensibility compared to Cre- controls. Interestingly, administration of galectin inhibitor (GI) partially but significantly suppressed aortic PWV in Cre+ mice compared to the Cre- and vehicle control groups (Cre- VC:2.2± 0.05; Cre- GI: 2.1±0.02; Cre+ VC: 3.5±0.2; Cre+ GI: 2.8± 0.04 m/s; P<0.01). Furthermore, ex-vivo aortic ring analysis with pin myography in response to contractile (serotonin) and relaxation [acetylcholine (Ach 10^-5M) and sodium nitroprusside (SNP 10^-5M)] agents showed significantly decreased contraction and relaxation in Cre+ mice compared to Cre- controls (Contraction: Cre+VC:9.1±0.9; Cre-VC:17±2.5mN; Relaxation Ach: Cre+VC:5% vs Cre-VC:66%; SNP: Cre+VC:70% vs Cre-VC:97%). However, galectin inhibition in Cre+ mice showed minimal response to Serotonin or Ach/SNP-induced aortic contraction and relaxation compared to vehicle or WT controls (Contraction: Cre-VC: 17±2.5; Cre-GI:10±1; Cre+VC:9±0.9; Cre+GI:7±0.2 mN; Relaxation: Ach-Cre-VC: 66%; Cre-GI:63%; Cre+VC:5%; Cre+GI:-7%/SNP-Cre-VC:97%; Cre-GI:97%; Cre+VC:70%; Cre+GI:58%).
Conclusion: These findings suggest that pharmacological inhibition of galectin partially suppressed SMC-Beclin-1 deficiency accelerated aortic stiffness in mice, as evidenced by decreased PWV.