2025 Volume 66 Issue 1 Pages 114-125
Oxidative stress and cardiomyocyte apoptosis are hallmarks of heart failure (HF) development. Plant homeodomain finger protein 8 (PHF8) is a histone demethylase downregulated in failing human hearts. Nevertheless, the potential role of PHF8 in HF remains unclear. Therefore, this study aimed to explore the biological action and molecular mechanism of PHF8 in HF.
A rat model of left anterior descending coronary artery (LAD) ligation-induced HF and a cardiomyocyte model of oxygen-glucose deprivation/reperfusion (OGD/R) were developed after gain- or loss-of-function experiments in rats and cardiomyocytes, respectively. Heart function indexes, such as left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular ejection fraction, and left ventricular fractional shortening, were detected. Changes in myocardial tissues were examined by pathological staining. Cardiomyocyte apoptosis and oxidative stress markers, such as malondialdehyde, reactive oxygen species, superoxide dismutase, and catalase, were examined. The relationship between PHF8 and forkhead box A2 (FOXA2) was analyzed by luciferase and chromatin immunoprecipitation-quantitative polymerase chain reaction assays.
PHF8 was downregulated in LAD-ligated rats and OGD/R-exposed cardiomyocytes. Following PHF8 upregulation, pathological changes in myocardial tissues and heart dysfunction were improved in LAD-ligated rats. Importantly, cardiomyocyte apoptosis and oxidative stress were diminished in vivo and in vitro upon PHF8 upregulation. Mechanistically, PHF8 increased FOXA2 expression in a histone demethylase-dependent manner. FOXA2 silencing abrogated the protective effect of PHF8 upregulation on cardiomyocytes against OGD/R-induced apoptosis and oxidative stress.
PHF8 exerts protective functions against cardiomyocyte apoptosis, oxidative stress, and heart dysfunction in HF, in correlation with FOXA2 upregulation. These results suggest that the PHF8/FOXA2 axis may be a promising therapeutic target to prevent HF.
