The Role of Mechanosensitive Signaling Cascades in Repair and Fibrotic Remodeling of the Infarcted Heart

Abstract

The adult mammalian heart has negligible regenerative capacity and heals through formation of a collagen-based scar. Repair of the infarcted heart requires stimulation of an inflammatory reaction and subsequent activation of matrix-secreting myofibroblasts. Perturbed myofibroblast function results in defective healing and may cause rupture and adverse dilative remodeling, whereas prolonged, excessive, or unrestrained fibrogenic actions following infarction may be associated with progression of fibrosis and development of heart failure. Mechanosensitive pathways are critically implicated in regulation of the cellular responses involved in repair, fibrosis, and adverse remodeling of the infarcted heart. In this chapter, we review the role of mechanical stress-mediated signals in scar formation and in fibrotic remodeling of the infarcted heart. Mechanosensitive signaling plays a critical role in stimulation of neurohumoral cascades, and in activation of growth factors in the infarcted heart, and is implicated, along with the release of biochemical mediators, in myofibroblast conversion and activation. In cardiac fibroblasts, integrin-mediated signals and mechanosensitive ion channels transduce stress-induced signaling cascades that activate matrix-synthetic programs. Interventions targeting mechanically stimulated cascades may hold promise as therapeutic strategies against adverse post-infarction remodeling.