Abstract 3063: Canonical And Noncanonical Heat Shock Factor 1 Signaling In Smooth Muscle Cells Promote Atherosclerotic Plaque Burden

Smooth muscle cells (SMCs) in atherosclerotic plaques undergo complex phenotypic modulation, characterized by migration from the aortic medial layer to the intima, proliferation, de-differentiation, and variable increases in molecular markers characteristic of macrophages, fibroblasts, osteogenic cells and mesenchymal stem cells. This transition is driven in part by cholesterol entering the endoplasmic reticulum (ER) and activating ER stress. The importance of ER stress-driven PERK signaling in atherosclerosis is underscored by the observation that SMC-specific deletion of Perk reduces lesion size by ~70% in hypercholesterolemic (HC) mice. HC mice harboring either an SM α-actin ( ACTA2 ) missense variant or SMC-specific deletion of the centrosomal scaffolding protein pericentrin ( PCNT ) have increased augmented plaque burden compared to their HC wildtype (WT) counterparts, despite having comparable serum lipid levels. We went on to demonstrate that both these genetic alterations increase SMC cytosolic stress and activation of canonical heat shock factor 1 (HSF1) signaling, which in turn increases HMG-CoA reductase (HMGCR) activity and cholesterol biosynthesis, ER stress, PERK signaling, SMC phenotypic modulation and finally, augments the plaque burden. We also noted another distinct pro-atherogenic form of HSF1 activation in SMCs: SMCs in culture exposed to high levels of exogenous cholesterol activate PERK signaling, but also consistently activate HSF1, and blocking PERK signaling prevents HSF1 activation, suggesting “noncanonical” HSF1 activation. While global loss of Hsf1 in HC mice reduces plaque burden, we generated tamoxifen-inducible SMC-specific Hsf1 -deficient mice ( Hsf1 SMC-/- ) to assess the role of HSF1 signaling in SMCs of HC mice. Hyperlipidemia was induced in these mice by a single injection of AAV- PCSK9 DY followed by a high fat diet for 12 weeks. En face aortic Oil Red O staining demonstrated that Hsf1 SMC-/- mice had 67% reduction in plaque size in the whole aorta (p=0.0007), compared to HC WT mice, similar to the results seen with SMC-specific Perk deficiency. These data suggest distinct roles of canonical and noncanonical HSF1 signaling in SMCs that contribute to atherosclerotic plaque burden.