Blockage of Pcsk6-mediated autophagy is involved in the protection of Znf667 against myocardial ischemia/reperfusion injury

The objective of this study is to elucidate the function and mechanism of Pcsk6 in myocardial ischemia/reperfusion (I/R) injury. Serum PCSK6 levels were increased in ST-segment elevation myocardial infarction patients following primary percutaneous coronary intervention (p < 0.0001) and positively correlated with cTnI (r = 0.511) and NT-proBNP levels (r = 0.464). Pcsk6 levels were elevated in myocardial tissues 6 h after I/R (p = 0.0001) and cardiomyocytes 12 h after hypoxia-reperfusion (H/R) (p < 0.0001). Pcsk6 knockdown reduced the LC3B-II/I ratio in myocardial tissues and H/R-treated cardiomyocytes (p < 0.0001 and p = 0.0020, respectively) and decreased INF/AAR in mice (p = 0.0303). Conversely, Pcsk6 overexpression increased the LC3B-II/I ratio (p = 0.0338) and reduced cell viability (p = 0.0293) under H/R. Znf667 was downregulated in H/R cardiomyocytes (p = 0.0096). Znf667 overexpression reduced wild-type Pcsk6 promoter activity (p = 0.0004) and Pcsk6 mRNA expression (p = 0.0011). Moreover, Znf667 overexpression reduced INF/AAR in mice (p = 0.0216) and the Nf-κB p-p65/total p65 ratio in H/R cardiomyocytes (p = 0.0164), which were restored by combined overexpression of Pcsk6 (p = 0.0005 and p = 0.0297). In H/R cardiomyocytes overexpressing both Znf667 and Pcsk6, BAY11-7082 increased cell viability (p = 0.0203) and reduced the LC3B-II/I ratio (p = 0.0146). In conclusion, Znf667 alleviates enhanced autophagy and myocardial I/R injury by transcriptionally suppressing Pcsk6. The current findings suggest that Nf-κB may be involved in this process and that PCSK6 may be a biomarker for assessing reperfusion injury.