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

Background

Myocardial infarction is followed by cardiac dysfunction, cellular death, and ventricular remodeling, including tissue fibrosis. S100A4 protein plays multiple roles in cellular survival, and tissue fibrosis, but the relative role of the S100A4 in the myocardium after myocardial infarction is unknown. This study aims to investigate the role of S100A4 in myocardial remodeling and cardiac function following infarct damage.

Methods and results

S100A4 expression is low in the adult myocardium, but significantly increased following myocardial infarction. Deletion of S100A4 increased cardiac damage after myocardial infarction, whereas cardiac myocyte-specific overexpression of S100A4 protected the infarcted myocardium. Decreased cardiac function in S100A4 Knockout mice was accompanied with increased cardiac remodeling, fibrosis, and diminished capillary density in the remote myocardium. Loss of S100A4 caused increased apoptotic cell death both in vitro and in vivo in part mediated by decreased VEGF expression. Conversely, S100A4 overexpression protected cells against apoptosis in vitro and in vivo. Increased pro-survival AKT-signaling explained reduced apoptosis in S100A4 overexpressing cells.

Conclusion

S100A4 expression protects cardiac myocytes against myocardial ischemia and is required for stabilization of cardiac function after MI.