State of change: epigenetic and mitochondrial regulation of cardiac fibroblast activation

Abstract

Cardiac fibroblasts (CFs) exist in a variety of states that contribute to either conserved or uncontrolled extracellular matrix (ECM) deposition. In healthy hearts, fibroblasts favor the homeostatic or quiescent state in which they work to maintain the ECM at a baseline level of activity. Acute or chronic injury in the form of myocardial infarction, hypertension, and heart failure induce CF activation via increased pro-oxidant, proinflammatory, and profibrotic stimuli secondary to hypoxia, cardiomyocyte cell death, or hemodynamic stress. In addition to the well-described signaling molecules that induce CF activation (e.g. transforming growth factor beta 1, angiotensin II, and reactive oxygen species), there are emerging concepts that describe mechanisms that regulate more nuanced transition between activation states. This review will discuss recent descriptions of heterogeneous populations of resident cardiac fibroblasts, states of fibroblast activation, and the roles for mitochondrial and chromatin accessibility in mediating transition to and persistence of the activated state.