Thoracic aortic aneurysms and dissections (TAAD) are interrelated cardiovascular diseases that carry high mortality. Current approaches to pharmacologic treatment of TAAD are ineffective, particularly in patients with sporadic disease not attributed to a genetic condition, such as Marfan syndrome. Although there is a critical need to develop new treatment strategies, a major barrier to this goal is a poor understanding of the molecular mechanisms that trigger and then promote aortic degeneration in sporadic TAAD. Therefore, the long-term goal of the investigators is to improve the understanding of the pathobiology of aortic wall degeneration in hope of developing new pharmacological strategies to prevent TAAD formation and progression. The overall objectives of this application are to determine the role of the NLRP3 inflammasome cascade, a multiprotein platform involved in amplifying intracellular stress responses, in promoting aortic destruction, and the extent to which this cascade represents a therapeutic target against TAAD. The central hypotheses are that the NLRP3-ASC- caspase-1 cascade promotes aortic degeneration by inciting protease-mediated extracellular matrix (ECM) destruction and promoting smooth muscle cell (SMC) contractile dysfunction, and that pharmacological inhibition of this cascade will prevent TAAD. These hypotheses will be tested through three specific aims: (1) Determine the effect of the inflammasome cascade on thoracic aortic wall structure and function, (2) Determine how the cascade promotes protease activation and SMC contractile dysfunction, and (3) Determine the extent to which pharmacological inhibition of the cascade prevents TAAD. Under the first aim, experiments using knockout mice will be conducted to determine whether the NLRP3 inflammasome cascade promotes aortic wall ECM destruction, contractile dysfunction and biomechanical failure. Under the second aim, studies with aortic SMCs will be performed to determine whether the cascade activates MMP-9 by directly cleaving two specific domains. In addition, protein interaction, cleavage, and contraction studies with SMCs will be conducted to determine whether the cascade promotes SMC contractile dysfunction by cleaving and degrading myosin heavy chain and tropomyosin. Under the third aim, experiments with two established mouse TAAD models will be conducted to determine whether pharmacological inhibitors of inflammasome activation (e.g. glyburide) will prevent TAAD development. The proposed research is significant because it will determine how the inflammasome cascade promotes TAAD development and the extent to which an inflammasome inhibitor can prevent TAAD. This research is innovative because it represents a new and substantive departure from the status quo, namely the current pharmacologic approaches to preventing sporadic TAAD progression. The development of a new, effective treatment would have an important positive impact by delaying or obviating invasive procedures in patients presenting with early-stage TAAD, suppressing disease progression in patients who are poor candidates for surgical treatment, and improving the durability of both open surgical and endovascular aortic repairs.
The proposed research is relevant to public health because thoracic aortic aneurysms and dissections are frequent causes of death in the United States, largely because current approaches to pharmacologic treatment are ineffective. The project is relevant to the NHLBI's mission because it focuses on treatment and prevention of life-threating cardiovascular disease; the development of a new, effective therapeutic agent would prevent aortic disease progression and save lives in patients with these conditions.
| Wu, Darrell; Ren, Pingping; Zheng, Yanqiu et al. (2017) NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation. Arterioscler Thromb Vasc Biol 37:694-706 |
