Acute and chronic exposures to environmental pollutants (EPs) like particulate matter (PM) impair cellular homeostasis and predispose to cardiovascular diseases (CVDs). Further, CVDs remain a major cause (60-80%) of EP-related mortality worldwide. Prior studies have documented that CVDs-promoting effects of EPs like PM involve systemic inflammatory responses, generation of reactive oxygen species (ROS), cardiotoxicity, premature cellular senescence, apoptosis and cardiopulmonary dysfunction. Our long-term research goal is to define the molecular basis of PM-induced CVDs and to develop novel therapy. The objective of this application is to determine the contribution of deregulated plasminogen activator inhibitor-1 (PAI-1) in EPs-induced CVDs and to test the efficacy of a small molecule inhibitor of PAI-1 in improvement of EPs-associated CVDs. Our central hypothesis is that that elevation of PAI-1 plays a pivotal role in PM-induced CVDs as it inhibits serine protease plasminogen activators (t-PA/uPA), decreases cellular quenching of ROS, promotes cellular dysfunction and cardiovascular injuries. Conversely, genetic or pharmacological inhibition of PAI-1 ameliorates PM-induced CVDs. The strong rationale behind formulating this hypothesis stems from the observations that an imbalance in tissue fibrinolytic system, due to altered expression of t-PA/uPA and PAI-1, is associated with the pathophysiology of endothelial dysfunction and CVDs including hypertension, arteriosclerosis, arrhythmias and myocardial infarction. Interestingly, EPs like PM inhibit t-PA and enhance the expression of potent t-PA inhibitor, PAI-1, and furthermore, a specific and potent small molecule inhibitor of PAI-1 effectively blocks oxidative stress-induced premature senescence and cellular dysfunction. However, the significance of PAI-1-t-PA/uPA pathway in development of EPs-induced CVDs and a “therapeutically relevant” function of PAI-1 inhibitor in preventing PM-induced CVDs have never been explored. This is an innovative and viable research project because the direct role of PAI-1-t-PA/uPA axis in EPs-induced CVDs will be explored for the first time using murine models with different dosage of global and cardiac specific PAI-1 gene. Importantly, the efficacy of a small molecule inhibitor of PAI-1 in treatment of EPs-induced CVDs will be tested. This proposal has immense impact in the field of CVDs and EPs research as it aims to identify therapies to reduce EPs-induced CVDs and associated morbidity and mortality. This project supports the mission of AHA as identification of a safe small molecule inhibitor of PAI-1 and its application in preclinical study will be helpful to develop novel therapeutics for the treatment of acute EP-induced CVDs and stroke in humans. This proposal is extremely significant as the expected outcome of the present innovative research is linked to the advancement of a larger body of knowledge as the elevation of PAI-1 is a major contributor to cellular dysfunction and is associated with numerous CVDs. If successful, the anticipated outcome of this project will accelerate therapies for EPs related CVDs targeting druggable PAI-1 and save millions of people worldwide.
|Effective start/end date||7/1/18 → 6/30/21|
- American Heart Association (18IPA34170365)