SAAM-1 senolytic vaccination alleviates atherosclerosis and cardiac dysfunction in mouse models

Abstract Introduction The elimination of senescent cells, termed "senolysis," has emerged as a novel and promising therapeutic strategy for mitigating various age-related pathologies, including cardiovascular diseases. Previously, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a "seno-antigen" using a public transcriptome database, which led to the development of a GPNMB-targeted senolytic vaccine. This vaccine selectively cleared senescent cells, improving diabetes, atherosclerosis, and age-related phenotypes in mice. Recently, through single-cell RNA-sequencing analysis, we discovered that senescence-associated adhesion molecule 1 (SAAM-1) strongly correlates with the senescent state in endothelial cells. Here, we establish SAAM-1 as a novel cell-surface seno-antigen and evaluate the efficacy of a SAAM-1-targeted vaccine in preclinical models of cardiovascular disease. Purpose To assess the therapeutic potential of SAAM-1 vaccination in alleviating cardiovascular pathology, specifically heart failure and atherosclerosis, in mouse models. Methods In a heart failure (HF) model, C57BL/6N mice vaccinated with SAAM1-VAC or cont-VAC at 8 and 10 weeks underwent transverse aortic constriction (TAC) or sham surgery at 13 wo. Echocardiography and heart sampling for histological and molecular biological analyses were conducted 2 weeks and 5 weeks after the surgery respectively. In an atherosclerosis model, ApoE knockout (KO) mice were subjected to a high-fat diet starting at 4 weeks of age and received SAAM-1 vaccine (SAAM1-VAC) or control vaccine (cont-VAC) at 8 and 12 weeks. Aortas were harvested at 18 weeks for histological and molecular biological analyses. Additionally, ApoE-KO mice were crossed with p16-luciferase (p16-Luc) reporter mice to track the senescence burden in the aorta. Results In the TAC model, SAAM-1 expression was markedly elevated in failing left ventricles, particularlly in endothelial cells. Interestingly, SAAM-1 vaccination significantly inhibited this increase, resulting in improvement of contractile dysfunction and left ventricular dilation. Additionally, this vaccination attenuated cardiac fibrosis and reduced the expression of senescence markers (p16, p21) and proinflammatory cytokines. In ApoE-KO mice, SAAM-1 vaccination substantially reduced p16-Luc signal in the aorta which indicates a decrease in senescence burden, and suppressed atherosclerosis progression alongside reduced expression of inflammatory markers. Conclusions Vaccination targeting SAAM-1 emerges as a novel and promising therapeutic strategy to mitigate age-related cardiovascular pathology, effectively addressing both heart failure and atherosclerosis in preclinical models.