Cardiac TNF Receptor-Associated Factor 7 Mediates the Ubiquitination of Apoptosis Signal-Regulating Kinase 1 and Aggravates Cardiac hypertrophy

Tumour necrosis receptor-associated factor 7 (TRAF7) belongs to the tumour necrosis factor receptor (TNFR)-associated factor family and plays an important role in biological processes. Previous studies have shown that TRAF7 mutations lead to congenital defects and malformations of the heart. However, the molecular mechanisms of TRAF7 in the underlying pathogenesis of pathological cardiac hypertrophy remain unknown. Here, we found that the expression of TRAF7 increased gradually during the development of hypertrophy. Accordingly, TRAF7 significantly exacerbated the phenylephrine (PE)-induced enlargement of primary neonatal Sprague Dawley rat cardiomyocytes (NRCMs), whereas TRAF7 knockdown alleviated the hypertrophic phenotype in primary cardiomyocytes. Cardiac-specific overexpression of TRAF7 accelerated hypertrophic phenotype in mice and cardiac-specific TRAF7 conditional knockout mice improved hypertrophic phenotype induced by transverse aortic constriction (TAC). Mechanistically, TRAF7 directly interacted with apoptosis signal-regulating kinase-1 (ASK1) and promoted ASK1 phosphorylation by mediating the K63-linked ubiquitination of ASK1 in response to PE stimulation, which then promoted ASK1 activation and downstream signalling during cardiac hypertrophy. Notably, the pro-hypertrophic effect of TRAF7 was largely blocked by the ASK1 inhibitor, GS4997. In summary, we identified TRAF7 as an essential regulator during cardiac hypertrophy, and modulation of the regulatory axis between TRAF7 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.