Thoracic aortic aneurysms and dissections (TAAD), particularly type A dissections, are a devastating disease, with an in-hospital mortality rate up to 25%. Although ascending aortic aneurysms and dissections (AADs) may result from genetic predispositions, more than 70% of cases are sporadic. Currently, surgical repair is the only available treatment. Development of pharmacological prevention agents remains a challenging task due to poor understanding of the cellular and molecular mechanisms responsible for pathogenesis of AADs. We have reported that postnatal deletion of smooth muscle cell (SMC) transforming growth factor-? type I receptors (Tgfbr1iko) induces AAD formation in male mice. Recently, we developed a novel X-linked Cre line that drives Tgfbr1iko and AAD formation in female mice with similar efficiency and severity compared to its parental Y-linked myh11-CreERTM strain. One of the histological hallmarks of AADs is chronic inflammation, characterized by progressive SMC depletion, immune cell infiltration, and matrix degradation. These events create a perfect environment for activation of the innate immunity. Specifically, molecules produced by dying SMCs can function as damage-associated molecular patterns to activate pathogen recognition receptors (PRRs) via autocrine and/or paracrine signaling, a scenario currently under rigorous experimental and clinical evaluation for other chronic conditions. Therefore, we explored activation of the innate immunity in our AAD models and obtained results as follows. 1) AAD formation was associated with RNA oxidation, upregulation of toll-like receptor (TLR)- 7, and SMC necroptosis. 2) AAD-, but not normal aorta-derived RNAs triggered inflammatory response in immune cells. 3) More importantly, treatment of mice with reagents inhibiting endosomal TLRs attenuated AAD formation. These novel findings led to our overall hypothesis that self-RNAs trigger TLR7-mediated danger signals to promote TAAD development. This hypothesis will be tested through two interrelated Specific Aims.
Specific Aim 1 will determine the contribution of self-RNAs to activation of innate immune injury and AAD formation. Studies under this Aim will address three key issues. 1) What makes self-RNAs pathogenic? 2) How self-RNAs regulate the RIPK3/pMLKL pathway to induce necroptosis of SMCs? 3) What is the role of necroptosis of SMCs in AAD formation? Specific Aim 2 will identify PRR(s) that sense self-RNAs to promote AAD formation. Experiments proposed under Specific Aim 2 will answer two key questions. 1) Are self-RNAs sensed by the same endosomal TLR member(s) in different type of cells across species (i.e. mouse vs. human)? 2) Is genetic or pharmacological inhibition of the responsible RNA-sensing TLR(s) sufficient to alter the course of AAD formation? Our novel AAD mouse models have placed us in a unique position to address these issues with mouse AADs of either gender. Completion of this project will provide a better understanding of the mechanisms that nourish chronic inflammation during AAD formation and may lead to a new direction for the development of pharmacological preventions against initiation and progression of AADs.
Although cells use danger signals as means for maintaining tissue homeostasis, dysregulation of the danger signals paradoxically causes further tissue damage. This project seeks to determine how self-RNAs produced by stressed and necrotic cells regulate the local immune response and nourish chronic inflammation in thoracic aortic aneurysms and dissections (TAADs), a devastating cardiovascular disease to which pharmaceutical treatments are currently unavailable. Completion of this project will provide a better understanding of the mechanisms that fuel the fire of chronic inflammation during TAAD formation and may lead to a new direction for the development of pharmacological preventions against TAAD progression.
