ATF3 is required for the prevention of cardiomyopathy via the regulation of mitochondrial oxidative stress
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Activating transcription factor 3 (ATF3) is a critical regulator for cellular stress responses and is implicated in stress-induced cardiac hypertrophy and fibrosis. However, the role of ATF3 in cardiomyopathy remains controversial. Here, we demonstrate that ATF3 plays a cardioprotective role by controlling mitochondrial oxidative stress in angiotensin II (Ang II)-triggered cardiomyopathy. The expression of ATF3 was significantly upregulated in hypertrophic hearts chronically infused with Ang II, which correlated with Ang II-treated cardiomyocytes. In neonatal mouse ventricular myocytes (NMVMs), Ang II-elicited hypertrophic responses were either aggravated or suppressed by ATF3 depletion or overexpression, respectively. Similar results were also obtained in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). To analyze the direct role of ATF3 in cardiomyopathy, we generated mice with a cardiomyocyte-specific ATF3 deletion using a tamoxifen-inducible Cre-recombinase (αMHC-MerCreMer/loxP) system. In response to Ang II infusion, mice with cardiomyocyte-specific ablation of ATF3 (ATF3 cKO) exhibited aggravated cardiac hypertrophy and fibrosis concurrent with decreased fractional shortening and ejection fraction. In addition, the transcriptome analysis of control and cKO hearts revealed alterations in genes related to mitochondrial function and organization. In particular, the expression of Sirt3/Sod2 transcripts, well known as a mechanism for regulating mitochondrial oxidative stress, was increased in Ang II-infused mice, which was downregulated by the depletion of ATF3, suggesting the cardioprotective function of ATF3 through the improvement of mitochondrial function. These results suggest that ATF3 may be a potential therapeutic target for hypertrophic cardiomyopathy.
