Abstract Body (Do not enter title and authors here): Atherosclerotic cardiovascular disease is the leading cause of death globally. Hypertension is the most significant risk factor for atherosclerosis. Despite aggressive lowering of cholesterol and blood pressure, up to 50% of patients suffer recurrent cardiac events. This “residual risk” is thought to be due to untreated, chronic inflammation. Recently, a phenomenon that facilitates long-lasting innate immune activation called ‘Trained Immunity’ has been identified. Trained Immunity is driven by epigenetic and metabolic reprogramming of innate immune progenitors in response to specific stimuli. This ‘priming’ of progenitors results in innate immune cell progeny that are epigenetically and transcriptionally rewired to mount an augmented inflammatory response. We hypothesize that hypertension induces trained immunity in myeloid progenitor cells, leading to persistent monocyte activation and increased atherosclerosis progression.

To study hypertension’s effects on hematopoietic stem and progenitor cells (HSPCs) in atherosclerosis, we induced angiotensin II (Ang II)-mediated hypertension in donor mice for 2 weeks, followed by bone marrow transplant from the hypertensive mice into irradiated atherosclerosis-prone Ldlr^-/- mice. After 10 weeks on a high-fat diet, we observed that Ang II-induced hypertensive marrow recipients had accelerated atherosclerosis compared to normotensive marrow recipients. Further, RNA-seq and ATAC-seq analysis of monocyte progeny from transplanted Ang II-trained HSPCs demonstrated durable transcriptional and epigenetic signatures indicative of Trained Immunity. In vitro treatment of HSPCs with Ang II before differentiation into macrophages led to an augmented pro-inflammatory cytokine response to LPS stimulation. We found that Ang II training activated Dectin-1, a receptor involved in other forms of immune training, and blocking of Dectin-1 inhibits the augmented cytokine response. Our results suggest that Ang II induces trained immunity of immune progenitors via a Dectin-1-mediated pathway. These findings represent a novel mechanism by which hypertension contributes to the long-term increased risk of atherosclerosis in hypertensive patients.