Immunosenescence accelerates atherosclerosis development in AAV-PCSK9 mouse model

Abstract Aging is a dominant risk factor for atherosclerotic cardiovascular disease and is associated with compositional and functional changes in our immune system, called immunosenescence. To gain insights into the impact of immunosenescence on atherosclerosis, we investigated plaque development and the immune landscape in an AAV-PCSK9 mouse model. Young (3 months) and aged (18 months) male C57Bl/6 mice received a single i.v. injection of a recombinant adeno-associated virus encoding murine PCSK9 (rAAV8-D377Y-mPCSK9) and were fed a Western-type diet (WTD) for 10 weeks to induce atherosclerosis. At sacrifice, cholesterol and serum PCSK9 levels showed no difference. Atherosclerosis development in the aortic root was significantly enhanced with 59% in aged compared to young mice. Additionally, plaques in aged mice showed a more advanced phenotype, with an increased collagen/macrophage ratio. While the T cell percentage declined in the periphery and lymphoid organs upon aging, leukocytes, including T- and B cells, increased within the aged aortic arch. Moreover, we observed a shift towards effector (memory) subsets, including Th1 cells and Tregs, with elevated cytokine production and a senescent phenotype within the T cell compartment of aged mice. We also observed increased percentages of splenic age-associated B cells, regulatory B cells and plasma cells in aged mice, which coincided with increased levels of circulating antibodies. In conclusion, aged WTD-fed AAV-PCSK9 mice displayed pro-atherogenic immune alterations, including elevated plaque inflammation, increased cellular senescence and impaired humoral immune responses, contributing to accelerated atherosclerosis development compared to young mice. Targeting or reversing age-associated immunity could represent a promising strategy to combat atherosclerotic cardiovascular disease. Graphical Abstract