Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

Abstract

Background: The thyroid hormone metabolite 3-iodothyronamine (T1AM) is rapidly emerging as promising compound of decreasing heart rate and lowering cardiac output. The aim of our study was to fully understand the molecular mechanism of T1AM on cardiomyocytes and its potential targets in cardiovascular diseases. Material/Methods: We developed an in vitro myocardial ischemia-reperfusion injury model of AC-16 cells by hypoxia-reoxygenation injury. Cell viability of AC-16 cells was detected using CCK-8 assay and apoptosis was detected by flow cytometry. RNA-seq was used to characterize the gene expression in H/R-induced AC-16 cells after T1AM treatment. The mRNA levels of FoxO1, PPARa, Akt, and GCK and the protein levels of PPARa, GCK, and components of the Akt/FoxO1 pathway were detected by qRT-PCR and Western blotting, respectively. Results: Exogenous T1AM increased the H/R-induced AC-16 cell viability in a relatively low concentration. A total of 210 DEGs, including 142 upregulated and 68 downregulated genes, were determined in H/R-induced AC-16 cells treated with or without T1AM. A Venn diagram showed 135 common DEGs. The FoxO signaling pathway was identified via KEGG enrichment analysis of these 135 DEGs. Moreover, T1AM mediated hypometabolism and reduced the apoptosis of H/R-induced AC-16 cells via the Akt/FoxO1 pathway. Conclusions: Exogenous T1AM protects against cell injury induced by H/R in AC-16 cells via regulation of the FoxO signaling pathway. Our results suggest that T1AM can play a preventive role in myocardial H/R injury and also provide new insight for clinical management of AMI patients.

3-iodothyronamine inhibits apoptosis induced by myocardial ischemia reperfusion via the Akt/FoxO1 signaling pathway

“…Our previous study examined the effects of T1AM on H/ R-induced AC-16 cells. Based on both RNA-seq and cellbased assays, T1AM was shown to mediate hypometabolism and exert protective effects on cardiomyocytes via regulation of the FoxO signaling pathway (12,15). However, limited studies have reported the protective role of T1AM in vivo.…”

“…Furthermore, it has therapeutic potential for the treatment of metabolic (10), cardiovascular (11,12), and neurological diseases (13,14). Our previous RNA-sequencing data and in vitro myocardiocytes model demonstrated that T1AM protects cardiomyocytes against hypoxia/reoxygenation (H/R) induced cell injury in AC-16 cells via regulation of the FoxO signaling pathway (15). Other studies have shown that administration of T1AM in the isolated heart limited MIRI (16).…”

3,5‐Diiodothyronine protects against cardiac ischaemia–reperfusion injury in male rats

“…However, T1AM produced a cardioprotective effect in isolated rat hearts in an experimental acute model of ischaemia-reperfusion injury, mediated by protein kinase C and the mitochondrial pathway (Frascarelli et al, 2011). Recently, it was shown that T1AM protected AC-16 cells against cell injury induced by hypoxia-reoxygenation via regulation of the FoxO signalling pathway (Zhou et al, 2020). Both metabolites are generated from decarboxylation and deiodination reactions and, therefore, the regulation of the local synthesis of these metabolites might also be important for their physiological effects (Louzada & Carvalho, 2018).…”

Meteorin-Like (METRNL) Attenuates Myocardial Ischemia/Reperfusion Injury-Induced Cardiomyocytes Apoptosis by Alleviating Endoplasmic Reticulum Stress via Activation of AMPK-PAK2 Signaling in H9C2 Cells

“…Myocardial ischemia is involved in the progression of multiple cardiovascular diseases including coronary artery disease, myocardial fibrosis, and heart failure [ 22 , 23 ]. Recently, METRNL, which is a newly discovered adipokine, was proven to be significantly associated with the pathogenesis of coronary artery disease [ 16 ].…”