Hypertension-associated Trained Immunity in Myeloid Cells is a Determinant of Atherosclerosis

PROJECT SUMMARY Hypertension is a leading modifiable risk factor for global mortality and a key driver of atherosclerotic cardiovascular disease (CVD). Despite aggressive lowering of cholesterol and blood pressure, up to 50% of patients still suffer recurrent cardiac events. While this “residual risk” is likely due to chronic inflammation, what drives inflammation once hypercholesterolemic and hypertensive stimuli have been resolved is poorly understood. Recently, a phenomenon known as trained immunity—in which innate immune cells form long- lasting memory—has been described. In training, an initial stimulus rewires the epigenome (i.e. enhancers) of myeloid precursors thereby maintaining them in a primed state so that their mature progeny mount an augmented response to a wide range of subsequent stimuli. We propose the novel concept that hypertension results in trained immunity that predisposes to inflammation and atherosclerosis independent of blood pressure. We have new preliminary data in support of this concept: 1) transplant of hematopoietic stem and progenitor cells (HSPCs) from angiotensin (Ang) II-induced hypertensive mice into irradiated Western Diet-fed low-density lipoprotein receptor deficient (Ldlr-/-) mice accelerates atherosclerosis, as compared to HSPCs from normotensive mice; 2) cellular metabolism and epigenome organization in monocytes differentiated from these HSPCs remain altered months after exposure to Ang II; 3) in vitro Ang II-trained myeloid cells have an augmented pro-inflammatory cytokine response and increased signaling downstream of Dectin-1 — a non-canonical receptor for Ang II implicated in other forms of trained immunity; 4) blocking Dectin-1, but not the canonical Ang II type 1 receptor (AT1R) prevents the Ang II-training phenotype in vitro; 5) polymorphisms in the gene for Dectin-1 associate with atherosclerotic and inflammatory vascular diseases in a human phenome-wide association study. Thus, we hypothesize that hypertension induces trained immunity by epigenetically rewiring immune progenitors via a Dectin-1 pathway, contributing to chronic unresolved inflammation and the long-term increased risk of atherosclerotic CVD associated with hypertension. We will address this hypothesis through the following specific aims: Aim 1. Determine how hypertension-induced training of myeloid progenitors rewires the mature monocyte epigenome to promote a pro-atherogenic cell state and enhanced T cell activation. Aim 2. Determine whether hypertension-induced trained immunity and augmented atherosclerosis are specific to Ang II. Aim 3. Establish the mechanism by which Ang II promotes trained immunity in myeloid cells.