Low Type 3 Deiodinase (DIO3) activity Post-Myocardial Infarction leads to a Greater Incidence of Heart Failure in Female Mice

Objective: Studies in male mice show that myocardial infarction (MI) leads to the upregulation of type 3 deiodinase (DIO3), the enzyme that inactivates thyroid hormones, which has been regarded as a predictor of poor outcomes after MI. Interestingly, a recent human study has shown a sex-specific regulation of DIO3 after an ischemic event, with women presenting a significant downregulation of this gene. Therefore, this study aims to investigate the biological importance of DIO3 activity on MI recovery in female mice. Methods: Female mice expressing a tamoxifen-inducible Cre-recombinase under the control of the cardiomyocyte-specific Myh6 promoter and carrying a floxed selenocysteine insertion sequence in the DIO3 gene were used to reduce heart DIO3 activity. Animals were treated with tamoxifen (1.5 mg, once daily, for 3 days). MI was induced via ligation of the left anterior descending coronary artery 4 weeks after tamoxifen treatment. Ejection fraction (EF) was measured at baseline, 2 weeks, and 4 weeks after MI induction using echocardiography. Animals were sacrificed 4 weeks post-MI, and heart mitochondrial respiration was measured using Oxygraph-2K. Results: Our data demonstrated that 4 weeks post-MI, females with low DIO3 heart activity show low EF compared to wild-type control mice. We also observed that the cardiac mitochondria of females with low DIO3 activity after MI had lower lipid-linked respiration compared to wild-type control mice. Discussion/Significance of Impact: Impaired cardiomyocyte mitochondrial function has been linked to a reduced ability to recover from MI. We found that lowering cardiac DIO3 activity in female mice caused a reduction in heart function and in cardiomyocyte mitochondrial respiration, suggesting these animals have a reduced ability to recover from MI. The data have important translational implications and clinical significance given that it challenges the current knowledge about DIO3 function after MI and will contribute to explaining why women face a 20% greater risk than men of developing heart failure after MI. Furthermore, it highlights the importance of DIO3 on female heart function since the human DIO3 gene is transcriptionally responsive to estrogen, and MI numbers are relatively low in premenopausal women but significantly increase after menopause. CTSA Grant UL1 TR002535, KL2 TR002534, & TL1 TR002533 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.