A Proposed Mechanism for Transcriptional Regulation of Cardiac Hypertrophy

Heidi M. Medford

Conventional medical therapies for treatment of hypertension center around symptom management, and this is due, in part, to limited understanding of the mechanisms responsible for hypertrophy, remodeling, and progression to heart failure. Cardiac hypertrophy can be physiological or pathological. Physiological cardiac hypertrophy occurs in response to exercise and pregnancy, while pathological cardiac hypertrophy results from mechanical stress such as pressure overload induced by hypertension; this form of hypertrophy is irreversible, and can eventually degenerate to heart failure. Approximately 2-5% of circulating glucose enters the hexosamine biosynthesis pathway, and the end result is posttranslational attachment of O-linked attachment of β-N-acetylglucosamine (O-GlcNAc) to cardiac proteins, which is increased in cardiovascular disease and heart failure; O-GlcNAc transferase (OGT) is the enzyme that catalyzes this addition. OGT is a singly encoded protein with three splice variants (110, 103, and 78 kDa), and hypertrophic signaling is blunted by O-GlcNAcylation of proteins by OGT. Although the OGT 110 kDa subunit has been characterized in a variety of cell and tissue types, cardiac OGT function and activity remains poorly understood. The aim of this dissertation was to investigate the roles of O-GlcNAc and OGT in physiological and pathological hypertrophy signaling, as well as their interaction with multiple hypertrophic signaling cascades such as the fetal cardiac gene program (FCGP), as well as histone deacetylase 4 (HDAC4) and CaMKIIδ. The dissertation consists of three original research studies, as well as a recently published literature review describing the role of OGT in heart failure. Through a variety of study designs including Western diet consumption, exercise, and hypertension/pressure overload, we have demonstrated that 110 kDa OGT is essential to the cardiac stress response. This dissertation has firmly established the involvement of the 110 kDa subunit of OGT with FCGP, HDAC4, and CaMKIIδ regulated hypertrophic signaling, as well as implicated OGT as being intricately involved with regulation of calcium signaling proteins. The findings described in this dissertation enhance the understanding of both the function and involvement of OGT in exercise and heart failure, which will promote the development of more effective therapeutic approaches to cardiomyopathy.

A Proposed Mechanism for Transcriptional Regulation of Cardiac Hypertrophy

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