Knockdown of the 110kDa Subunit of OGT Dysregulates Cardiac Remodeling in Response to Pressure Overload

Abstract

Hypertension causes pathological cardiac hypertrophy and heart failure, but the mechanisms underlying this process are poorly understood. The attachment of O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) to serine/threonine amino acids by O‐GlcNAc transferase (OGT) is increased in cardiovascular pathology; OGT is singly encoded with three splice variants (110, 103, and 78 kDa). Hypertension incites pathological cardiac remodeling via aberrant calcium‐signaling and induction of the pro‐hypertrophic fetal cardiac gene program (FCGP). Activity of cardiac specific calcium‐bound calmodulin kinase II (CaMKIIδ) and histone deacetylase 4 (HDAC4) is altered by phosphorylation and O‐GlcNAcylation, and interactions between these proteins regulate cardiac hypertrophy. We used a cardiomyocyte‐specific OGT knockdown (OGTKD) mouse lacking 110kDa OGT, along with transaortic constriction (TAC), to investigate the effects of OGTKD and pressure overload (PO) on HDAC4 phosphorylation by CaMKIIδ. OGTKD mice exhibited extremely low postoperative survival, and HDAC4 and CaMKIIδ reacted oppositely to OGTKD by increasing and decreasing, respectively. OGTKD mice exhibited pathological hypertrophy independent of surgery, were cachexic, and OGTKD‐TAC mice weighed less than OGTKD‐sham mice (p=0.05). Calcium signaling was altered in OGTKD‐TAC hearts, and the FCGP was induced in OGTKD and TAC (p=0.05). These data suggest that 110kDa OGT is essential to prevent pathological cardiac remodeling and also for the cardiac stress response to PO.