Project Summary Acute myocardial infarction (AMI) is the leading cause of death in post-menopausal women, but how age- associated estrogen loss impacts the intersection of cardiac ischemic-reperfusion (I/R) injury, NLRP3 inflammasome signaling and subsequent AMI pathogenesis is untested. Promising feasibility data suggest that NLRP3 inflammasome hyperactivation and dysregulated cardiac mitochondrial quality control may create a toxic feed forward circuit to exacerbate proinflammatory responses and AMI progression in aged females. Age- associated chronic inflammation may amplify oxidative stress through impaired macrophage polarization. We will identify and characterize key age-associated changes in NLRP3 immune signaling that promote pyroptosis and infarct progression, and determine whether insufficient cardiac mitophagy is a driver of NLRP3 inflammasome hyperactivation following I/R injury in aged females (Aim 1). We will next determine if acute NLRP3 inflammasome suppression using a small molecule inhibitor, with and without macrophage depletion, confers cardioprotection through a mechanism involving reparative M2 macrophage phenotypic expression and protective cardiac mitochondrial quality control (Aim 2). We propose that targeted NLRP3 inflammasome inhibition will rescue the post-menopausal aged heart through unique and overlapping mechanisms involving cardiac macrophage polarization, mitophagy, and limiting mitochondrial-derived danger associated molecular patterns (DAMPs). The proposed studies are a logical extension of ongoing work in our laboratory, which seeks to define the effects of age-associated estrogen loss on cardiac I/R injury. F344 female rats will be ovariectomized at 15 mo and aged to 24 mo to better mimic human menopause, NLRP3 knock out rats for proof of concept, and adult and aged male rats for clinical comparison. Coronary artery ligation will be used to induce AMI with variable reperfusion over 7 days to test our specific aims in cardiac immune cell subsets and mitochondria. The findings from this study will be invaluable in establishing a role for NLRP3 inflammasome- mediated regulation of I/R injury in the aged female heart and strongly support the NLRP3 inflammasome as a therapeutic target for AMI reduction in older post-menopausal women. We will determine, for the first time, the contribution and mechanism by which NLRP3 inflammasome hyperactivation impacts vulnerability to AMI in aged female (and male) rats.
|Effective start/end date||5/1/21 → 1/31/22|
- National Institute on Aging: $240,750.00