All cells of the body are under some form of mechanical load and these forces are part of the factors defining cell type specificity. The mechanical environment influences cellular behavior and is the basis of mechanobiology. The forces acting on cells must be met with a cellular response, as the input signals are transduced to molecular mechanisms that drive gene regulation. In the heart, the distinct roles of cardiomyocytes and fibroblasts, as fibroblasts enforce tissue stiffness homeostasis through extracellular matrix maintenance and cardiomyocyte contraction-relaxation cycles work against this stiffness with every heartbeat, enable each to respond to cardiac stressors through differential gene expression, changing their cellular physical phenotype. At the cellular level, cardiac hypertrophy is a growth of the cardiomyocyte (without proliferation) and increased interstitial fibrosis, and these phenotypes are the result of changes to gene expression. While the gene expression program induced by cardiac hypertrophy is well documented, this dissertation unravels mechanosensitive mechanisms activated by changes to the myocardial environment and cellular forces driving dysfunctional gene regulation perpetuating cardiac disease. Gene translation ends in the nucleus; however, it does not always start there. We viewed gene expression as an end point, being influenced by a number of factors outside the nucleus, including metabolism, nucleoskeletal, cytoskeletal, sarcomere organization, sarcolemmal signal transduction pathways, and the tissue environment. In examining transcriptional influence outside the nucleus, we first summarize the bidirectional effect of metabolic and gene regulation dysfunction in heart disease, as metabolic substrates and intermediates impact cardiac epigenetics and chromatin stores information. We report our findings from our pressure overload induced cardiac hypertrophy studies, demonstrating cardiomyocyte cellular remodeling influences nucleoskeletal ultrastructure through the expression of the structural and chromatin binding protein Lamin A/C. We phenotypically characterize an [alpha]1-adrenergic model of cardiac hypertrophy and investigate cell specific mechanism driving tissue remodeling and cellular mechanosensitive pathways underlying pathological stress. Through these studies, we explore the cardiac stressors that remodel the heart tissue during hypertrophy and the cellular mechanisms altering the cellular phenotype through gene regulation.