Unraveling tissue level regulation of thyroid hormone and its role in sex differences in cardiovascular health

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading global cause of death, claiming approximately 17.9 million lives annually. Women face a significantly higher risk of heart failure or mortality following a heart attack than men, yet the molecular mechanisms behind this disparity remain poorly explored. This research aims to determine

the role of thyroid hormones (TH), an underexplored sexually dimorphic risk factor for female heart failure development, with a primary focus on its tissue-level regulation. TH significantly influences the cardiovascular system, and the higher prevalence of thyroid disease in women highlights its potential impact on female heart

health. Specifically, the study will concentrate on type 3 deiodinase (DIO3), which regulates TH levels within tissues. Recent findings from my lab show a sexual dimorphism in Dio3 expression in the heart. We have also demonstrated that female mice with Dio3 deficiency exhibited compromised cardiac function, including a

reduced ejection fraction, altered mitochondrial substrate utilization, and impaired recovery from myocardial infarction. These results underscore the protective role of Dio3 in the female heart and the importance of Dio3- dependent tissue-level TH regulation. This proposal aims to determine the role of Dio3 in cardiovascular health

outcomes in females. The overarching hypothesis is that cardiac Dio3 expression is regulated in a sex-specific manner, playing a pivotal role in driving sex-specific outcomes in cardiovascular health. In Aim 1, we will investigate whether Dio3 expression post-MI differs between sexes, potentially contributing to higher heart

failure susceptibility in females. In Aim 2, we will determine the interplay between estrogen and Dio3 in influencing cardiovascular function in female mice. This aim hypothesizes that low estrogen levels reduce Dio3 activity in female mouse hearts, impairing myocardial function. The study also investigates Dio3's role in

mediating estrogen's cardioprotective effects on cardiovascular function. Together, these aims will address crucial knowledge gaps regarding thyroid dysfunction and the sexually dimorphic onset of heart failure, aligning with priorities identified by the NHLBI Working Group. Beyond enhancing our understanding of sex-specific

factors in cardiovascular health, this work will provide vital scientific and technical training to support Dr. Teixeira's independent program. Ultimately, it will improve women's cardiovascular health, reduce disparities, and advance cardiovascular science.