Cardiac
fibrosis is the pathological remodeling of the extracellular matrix (ECM) in response to stresses such as pressure overload or injury. While initially adaptive, myocardial remodeling and subsequent
fibrosis causes increased wall stiffness,
arrhythmias, cardiac dysfunction, and eventually
heart failure. Though the disease processes and origins may differ, excess deposition of
fibrillar collagens type I and III characterizes
fibrosis in the heart, lungs, kidneys, liver, and skin. Under normal physiological conditions, high tensile strength
collagen fibers maintain cardiac structural integrity, connect individual cardiomyocytes, transmit contractile force, and resist deformation and
rupture of the ventricle during systole. Various factors contribute to the development of
fibrosis by altering expression of ECM genes, including increased synthesis of pro-inflammatory
cytokines, alterations in the levels of circulating
hormones, and mechanical strain resulting from ECM degradation. This review focuses on the transcriptional mechanisms governing expression of the major cardiac
collagen, type I. Key cis- and trans-acting regulators of
collagen I gene expression are discussed. Surprisingly, relatively few transcriptional regulators of
collagen synthesis have been identified specifically in cardiac fibroblasts. However, key players have been identified in other tissue and cell types, and are important to consider in elucidating the molecular mechanisms underpinning
collagen gene expression in the heart in both health and disease.