Pathophysiological and clinical significance of hepatokine Fetuin-A and myocardial N-myristoylation in heart failure

Heart failure (HF) is a systemic syndrome in which myocardial remodeling and multiorgan dysfunction exacerbate each other. This review focuses on the hepatokine Fetuin-A and the post-translational modification N-myristoylation in HF. Regarding Fetuin-A, we first demonstrated that circulating Fetuin-A levels were significantly lower in HF patients than in control subjects without structural heart disease. This reduction was associated with hepatic hypoperfusion. In a prospective study of 202 HF patients who underwent cardiopulmonary exercise testing, the combination of lower Fetuin-A and impaired exercise tolerance was independently associated with increased risk of cardiac events, suggesting that Fetuin-A could serve as a novel mediator of cardiac-hepatic-peripheral interaction. Regarding N-myristoylation, expression of N-myristoyltransferase 2 (NMT2) was significantly reduced in failing hearts. Cardiac-specific NMT2 knockdown exacerbated cardiac dysfunction, whereas AAV9-mediated NMT2 gene transfer attenuated cardiac remodeling and HF. Click chemistry-based proteomics identified MARCKS as a crucial substrate, and N-myristoylation of MARCKS prevented pathological hypertrophy by promoting its membrane localization, thereby suppressing CaMKII-HDAC4 signaling. These findings indicate that Fetuin-A and NMT2-dependent N-myristoylation play important roles in HF pathophysiology and represent potential novel therapeutic targets.