Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure

Yusuke Tomita; Fumiya Anzai; Tomofumi Misaka; Ryo Ogawara; Shohei Ichimura; Kento Wada; Yusuke Kimishima; Tetsuro Yokokawa; Takafumi Ishida; Yasuchika Takeishi

doi:10.1016/j.jacbts.2023.06.006

Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure

JACC Basic Transl Sci. 2023 Sep 6;8(10):1263-1282. doi: 10.1016/j.jacbts.2023.06.006. eCollection 2023 Oct.

Authors

Affiliations

¹ Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
² Department of Community Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.

Abstract

Protein diversity can increase via N-myristoylation, adding myristic acid to an N-terminal glycine residue. In a murine model of pressure overload, knockdown of cardiac N-myristoyltransferase 2 (NMT2) by adeno-associated virus 9 exacerbated cardiac dysfunction, remodeling, and failure. Click chemistry-based quantitative chemical proteomics identified substrate proteins of N-myristoylation in cardiac myocytes. N-myristoylation of MARCKS regulated angiotensin II-induced cardiac pathological hypertrophy by preventing activations of Ca²⁺/calmodulin-dependent protein kinase II and histone deacetylase 4 and histone acetylation. Gene transfer of NMT2 to the heart reduced cardiac dysfunction and failure, suggesting targeting N-myristoylation through NMT2 could be a potential therapeutic approach for preventing cardiac remodeling and heart failure.

Keywords: N-myristoylation; cardiac remodeling; gene therapy; heart failure; post-translational modifications.