Molecular Signaling Mechanisms of Myocardial Stretch: Implications for Heart Disease

Abstract

With every heartbeat, myocardial cells are subjected to substantial mechanical stretch. Stretch is a potent stimulus for growth, differentiation, migration, remodeling and gene expression. Mechanical load is a major cause of cardiac hypertrophy. Since the initial observation of stretch-induced growth, our understanding of this complex field has been steadily growing, but remains incomplete. The mechanisms by which myocardial cells convert mechanical stimuli into biochemical signals that result in physiologic and pathological changes remain to be completely understood. Integrins, caveolae and focal adhesions have been shown to have important mechanosensing roles in cardiac myocytes. Downstream effectors activated by mechanosensors include guanine-nucleotide binding proteins (G-proteins), mitogen-activated protein (MAP) kinases, Janus-associated kinase/signal transducers and activators of transcription (JAK/Stat), protein kinase C (PKC) and protein kinase B/Akt pathways. Multiple levels of crosstalk exist between these pathways. Early studies have implicated most of these pathways in cardiac injury and growth response, however, more recent advancements in the development of kinase-specific inhibitors and genetically-engineered animal models have revealed significant new insights. Recent studies suggest that acute mechanical stretch activates protective pathways including c-jun N-terminal kinase (JNK) and Akt as a tolerance response, rather than injury-related signaling cascades such as p38 MAP kinase. However, chronic stretch/mechanical load creates an imbalance that favors the injury related pathway by an unknown mechanism in the myocardium. The following chapter provides an overview of the fundamental processes of stretch-activated mechano-signaling in myocardial cells, and recent advances in our understanding of this increasingly important field.