Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

The intact heart undergoes complex and multiscale remodelling processes in response to altered mechanical cues. Remodelling of the myocardium is regulated by a combination of myocyte and non-myocyte responses to mechanosensitive pathways, which can alter gene expression and therefore function in these cells. Cellular mechanotransduction and its downstream effects on gene expression are initially compensatory mechanisms during adaptations to the altered mechanical environment, but under prolonged and abnormal loading conditions, they can become maladaptive, leading to impaired function and cardiac pathologies. In this Review, we summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. Developments in systems modelling of the networks that regulate gene expression in response to mechanical stimuli should improve integrative understanding of their roles in vivo and help to discover new combinations of drugs and device therapies targeting mechanosignalling in heart disease. In this Review, the authors summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. They also discuss the use of systems modelling to discover new therapies to target mechanosignalling in heart disease. Key points The complex remodelling processes in the myocardium are regulated by mechanical signals that are sensed and transduced into transcriptional responses by cardiac myocytes and fibroblasts. Mechanosensitive pathways regulate expression of genes that encode proteins mediating cardiac myocyte hypertrophy, myofibroblast differentiation and remodelling of the extracellular matrix. Mathematical systems models are beginning to address outstanding challenges regarding how cardiac cells integrate complex mechanical and biochemical signals to coordinate gene expression and cell remodelling. Integrative experimental and computational mechanotransduction studies should provide further insights into mechanisms and potential therapies for mechano-based diseases, including chronic tissue and chamber pathological remodelling.