Heart disease is the number one killer in developed nations. Heart failure, resulting from many different etiologies, is the inability of the heart to supply blood to the organism, and is eventually deadly. Due to the limited self-renewal capacity of cardiac myocytes, repairing the damaged myocardium and improving cardiac function is a major challenge. Additional novel, effective strategies to induce cardiac repair are essential to stave off the pathologies that will result in heart failure. Stimulating the induction of endogenous repair-promoting cardiac proteins may be one effective strategy for inducing cardiac repair. Stress-induced proteins, such as the nodal ER stress response transcription factor ATF6, and the ATF6-inducible secreted proteins, such as HMGB1 and MANF, as well ATF6-inducible, anti-hypertrophic proteins, such as synoviolin, are attractive therapeutic candidate proteins that are upregulated as a result of many cardiac pathologies. Elucidating how such candidate proteins are upregulated, as well as determining their mechanisms of action will shed light on the endogenous repair machinery of the heart, which will contribute to the future development of novel therapeutics for cardiac repair and functional recovery. Consequently, the research projects detailed in this dissertation were intended to further our understanding of the molecular basis of heart disease, while providing new insights into viable therapeutics for heart failure.