Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

Abstract

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.

Fig. 1. Major mechanosensitive mechanisms and pathways in cardiac fibroblasts and myocytes.

Mechanical signals that act on the extracellular matrix (ECM) and cell membranes and internally on the cytoskeleton and nucleus initiate complex molecular signalling cascades, leading to changes in gene expression and protein synthesis in both cell types. Direct and indirect interactions between cells also mediate these responses. The net result of the changes in the mechanical cues is tissue remodelling and, in many cases, pathophysiological outcomes.

Fig. 2. Systems model of the cardiac myocyte signalling network.

The model predicts how mechanical stretch is sensed by nine proteins to regulate transcription factors, protein synthesis, cell size and gene expression of NPPA (encoding atrial natriuretic peptide), NPPB (encoding B-type natriuretic peptide), ATP2A2 (encoding sarcoplasmic/endoplasmic reticulum calcium ATPase), MYH6 (encoding α-myosin heavy chain), MYH7 (encoding β-myosin heavy chain), ACTA1 (encoding skeletal α-actin), GJA1 (encoding connexin 43) and AGT (encoding angiotensinogen). AND logic gates indicate multiplicative activation or inhibition of the downstream node. Adapted from REF., CC-BY-4.0 (https://creativecommons.org/licenses/by/4.0/), and details of the model logic can be found in this publication.