Interplay of myocardial infarction, inflammation and clonal hematopoiesis of indeterminant potential in aged female rats
Description: Acute myocardial infarction (AMI) is a leading cause of mortality among the elderly in the United States, with postmenopausal women at a heightened risk of recurrent AMI and heart failure compared to age-matched men. Although reperfusion therapy is commonly used to treat AMI, it can also lead to ischemia/reperfusion (I/R) injury, exacerbating heart damage through inflammation-driven cell death. The NOD-like receptor with pyrin containing domain 3 (NLRP3) inflammasome has been implicated in the pathogenesis of immune-mediated I/R injury. Here, we propose that impaired macrophage infiltration and polarization and NLRP3 inflammasome hyperactivation contribute to increased AMI in aged females. Female F344 rats, both adult (5-6 mo) and aged (22-24 mo), will undergo coronary artery ligation (CAL; 31min ischemia followed by 24 hr reperfusion) to simulate AMI in vivo. In Aim 1, we will assess infarct size using TTC staining and evaluate systemic inflammation by measuring serum cytokine levels. NLRP3 inflammasome activation will be analyzed via Western Blot and RT-qPCR by readouts such as caspase-1, IL-1ß, and IL-18. Additionally, cardiac macrophage subtypes and phenotypes will be assessed using advanced flow cytometry (Cytek Aurora) and single-cell RNA sequencing. In Aim 2, we will explore the relationship between of the NLRP3 inflammasome hyperactivation, clonal hematopoiesis of indeterminate potential (CHIP) and AMI. Whole-genome sequencing will be utilized to screen for CHIP mutations in bone marrow and peripheral blood of adult and aged female rats with and without AMI. NLRP3 inflammasome inhibition is hypothesized to mitigate impaired macrophage polarization, reduce AMI, and decrease CHIP prevalence in aged. The goal of these studies is to inform new insights into mechanisms of cardiac inflammation and injury in a model aged of female aigng. By elucidating the interactions between NLRP3 inflammasome activity, macrophage polarization, AMI, and CHIP with age-related estrogen loss, this study seeks to inform the development of targeted immune therapies to improve cardiovascular health in elderly post-menopausal women.
Funder: American Heart Association
Amount: $69,550
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2025-07-01
End date: 2027-06-30
Investigators: Junyao Yuan, Junyao Yuan
Institution: The Pennsylvania State University
Funded outputs count: 0
Funder award ID: 25PRE1411245
OpenAlex ID: G3148796596