Focal adhesion kinase in cardiac development and disease

In the United States, nearly 80 million adults are affected by cardiovascular disease. The spectrum of disease range from congenital structural defects to acquired structural changes in response to an increased hemodynamic load on the heart, myocardial infarction, or hormonal imbalance. Cardiovascular disease accounts for significant amounts of morbidity and mortality and is currently the number one cause of death in the U.S. Congenital heart disease is the most common cause of infant death from birth defects. Genetic studies in lower vertebrates have been critical to the understanding of the specific factors required for heart development. These studies suggest that cardiac abnormalities may be mediated by abnormal regulation of transcription factors. Although several transcription factors involved in cardiac development have been elucidated, much regarding specific signaling pathways implicated in abnormal cardiogenesis is still unknown. Acquired cardiac disease can occur in response to various stimuli. For example, an increased hemodynamic load can result in compensatory hypertrophic remodeling and may progress to pathologic hypertrophy. A common manifestation of this pathologic process is a constellation of symptoms known as congestive heart failure. Focal Adhesion Kinase (FAK) is responsible for a variety of biological functions including cell adhesion, migration, proliferation, and survival. Several studies demonstrated a role for FAK binding partners and/or for upstream activators of FAK throughout cardiac development and disease. However, since germline deletion of FAK results in early embryonic lethality, it is difficult to study the specific role for FAK in cardiac development and disease. Therefore, we addressed this issue by creating several mouse models which express tissue specific expression of FAK, or its dominant negative FAK-related non-kinase (FRNK). We used these mice to investigate the role of FAK in cardiogenesis, anabolic growth, and cardiac disease. Collectively, these conditional mouse models demonstrated that FAK activity and/or its expression is required for cardiomyocyte proliferation throughout development, is dispensable for anabolic growth of the heart, and is necessary and sufficient for the induction of cardiac hypertrophy. Further characterization of the precise signaling pathways downstream of FAK may lead to targets for future therapeutic intervention to treat congenital and acquired heart disease