Role of GALNT4 in protecting against cardiac hypertrophy through ASK1 signaling pathway

• Published in: Cell death & disease 2021-10, Vol.12 (11), p.980-980, Article 980
• Main Authors: Zhang, Bin-Bin, Gao, Lu, Yang, Qin, Liu, Yuan, Yu, Xiao-Yue, Shen, Ji-Hong, Zhang, Wen-Cai, Han, Zhan-Ying, Chen, Shao-Ze, Guo, Sen
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/51; 38; 38/1; 38/77; 38/79; 631/337/475/2290; 692/699/75/230; 82; 82/80; Animals; Antibodies; Aorta; Biochemistry; Biomedical and Life Sciences; Cardiomegaly - genetics; Cardiomyocytes; Cell Biology; Cell Culture; Dimerization; Disease Models, Animal; Fibrosis; Humans; Hypertrophy; Immunology; Kinases; Life Sciences; Male; MAP kinase; Mice; N-acetylgalactosaminyltransferase; N-Acetylgalactosaminyltransferases - metabolism; Phenotypes; Phenylephrine; Phosphorylation; Polypeptide N-acetylgalactosaminyltransferase; Protein Interaction Domains and Motifs - genetics; Signal Transduction
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04222-5

Pathological myocardial hypertrophy is regulated by multiple pathways. However, its underlying pathogenesis has not been fully explored. The goal of this work was to elucidate the function of polypeptide N-acetylgalactosaminyltransferase 4 (GALNT4) in myocardial hypertrophy and its underlying mechanism of action. We illustrated that GALNT4 was upregulated in the models of hypertrophy. Two cardiac hypertrophy models were established through partial transection of the aorta in GALNT4-knockout (GALNT4-KO) mice and adeno-associated virus 9-GALNT4 (AAV9-GALNT4) mice. The GALNT4-KO mice demonstrated accelerated cardiac hypertrophy, dysfunction, and fibrosis, whereas the opposite phenotype was observed in AAV9-GALNT4 mice. Similarly, GALNT4 overexpression mitigated the degree of phenylephrine-induced cardiomyocyte hypertrophy in vitro whereas GALNT4 knockdown aggravated the hypertrophy. In terms of mechanism, GALNT4 deficiency increased the phosphorylation and activation of ASK1 and its downstream targets (JNK and p38), whereas GALNT4 overexpression inhibited activation of the ASK1 pathway. Furthermore, we demonstrated that GALNT4 can directly bind to ASK1 inhibiting its N-terminally mediated dimerization and the subsequent phosphorylation of ASK1. Finally, an ASK1 inhibitor (iASK1) was able to reverse the effects of GALNT4 in vitro. In summary, GALNT4 may serve as a new regulatory factor and therapeutic target by blocking the activation of the ASK1 signaling cascade.