Areas of Research
The main focus of our research is aortic aneurysms and dissections, life-threatening diseases caused by progressive degeneration of the aortic wall. We have several ongoing projects investigating the mechanisms of aortic destruction, repair, and remodeling. The ultimate goal of our research is to develop pharmacological treatments to prevent progressive aortic degeneration, maladaptive remodeling, and disease progression.
Detrimental Effects of Ciprofloxacin on the Aortic Wall
Despite concerns raised by population-based cohort studies, the U.S. FDA previously determined that there was not sufficient evidence to issue a warning that the use of fluoroquinolone antibiotics increases the risk of aortic aneurysm, dissection, and rupture. To address the gap in evidence, Drs. LeMaire and Shen conducted experiments to test the hypothesis that ciprofloxacin impairs aortic homeostasis and renders the aortic wall susceptible to stress-induced development of aortic aneurysm and dissection.
In an established mouse model of aortic disease, they found that ciprofloxacin significantly increased susceptibility to challenge-induced aortic dissection and rupture compared to controls. They also found that ciprofloxacin decreased lysyl oxidase expression and activity, increased matrix metalloproteinase levels and activity, and increased elastic fiber fragmentation and cell injury. These findings, reported in JAMA Surgery, supported concerns raised in observational clinical studies and suggested that the drug should be used with caution in patients with aortic dilatation and those at high risk for aortic aneurysm and dissection.
By the end of 2018, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency issued a warning for fluoroquinolones, citing this paper. The U.S. FDA followed with a similar warning.
Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections
The overall objective of this project is to systematically define the role of the NLRP3 inflammasome cascade, a multiprotein platform involved in amplifying intracellular stress responses, in promoting aortic destruction, and to determine the extent to which this cascade represents a therapeutic target against aortic aneurysms and dissections.
This project is currently supported by NIH NHLBI R56 and R01 awards. R56 HL127111 and R01 HL127111 respectively.
Targeting ER Stress to Treat Thoracic Aortic Aneurysms and Dissections
The objectives of this project are to determine the role of endoplasmic reticulum stress and the endoplasmic reticulum stress sensor STING in aortic destruction, and the extent to which this mechanism represents a therapeutic target against aortic aneurysms and dissections.
This project is currently supported by an NIH NHLBI R01 award. R01 HL131980
Destructive Role of ADAMTS-4 in Aortic Aneurysms and Dissections
The goal of this project is to determine the role of ADAMTS-4 in aortic destruction and dysfunction and evaluate the effect of ADAMTS-4 inhibitors in prevention and treatment of aortic disease.
This project is currently supported by an American Heart Association Grant-in-Aid. 15GRNT23040007