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
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.