The Cellular and Molecular Response of Cardiac Myocytes to Mechanical Stress

Abstract

External load plays a critical role in determining muscle mass and its phenotype in cardiac myocytes. Cardiac myocytes have the ability to sense mechanical stretch and convert it into intracellular growth signals, which lead to hypertrophy. Mechanical stretch of cardiac myocytes in vitro causes activation of multiple second messenger systems that are very similar to growth factor-induced cell signaling systems. Stretch of neonatal rat cardiac myocytes stimulates a rapid secretion of angiotensin II which, together with other growth factors, mediates stretch-induced hypertrophic responses in vitro. In this review, various cell signaling mechanisms initiated by mechanical stress on cardiac myocytes are summarized with emphasis on potential mechanosensing mechanisms and the relationship between mechanical loading and the cardiac renin-angiotensin system.

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

“…36,37 Mechanical stress itself has a role in initiating hypertrophic responses in myocytes by activating multiple signaling pathways. 38,39 In contrast, the circulating and autocrine/paracrine humoral factors, such as angiotensin II, TGF-b and MCP-1, have been implicated in hypertensive myocardial fibrosis. 23,25,[40][41][42] Further research is necessary, to determine the mechanism by which simvastatin induces the different effects between myocyte hypertrophy and myocardial fibrosis in this model.…”

Mechanoregulation of gene expression in fibroblasts

“…The involvement of Rho activity in the formation FAs and stress fibers through syndecan-4 signaling has also been suggested (Saoncella et al, 1999;Couchman et al, 2001). Besides all signaling molecules described above, stretch-activated ion channels are considered to be candidates for mechanotransduction mechanisms (Hu and Sachs, 1997;Sadoshima and Izumo, 1997). One of the earliest signals that are generated after application of mechanical stretching is the influx of calcium ions through stretch-activated ion channels in fibroblasts (Wu et al, 1999).…”

“…Activation and transportation of immediate early response genes such as cfos and transcription factor NF-κB, which can bind to mechanoresponsive ECM genes, are suggested as two of the primary responses to mechanical loads (Khachigian et al, 1995;Sadoshima and Izumo, 1997;Mercurio and Manning, 1999a,b;Chen et al, 2003;Xiao, 2004). Transcription and synthesis of nuclear factors such as early growth response-1 (EGR-1) that can transactivate a specific ECM gene are considered secondary responses to mechanical loads (Schwachtgen et al, 1998;.…”

“…Transcription and synthesis of nuclear factors such as early growth response-1 (EGR-1) that can transactivate a specific ECM gene are considered secondary responses to mechanical loads (Schwachtgen et al, 1998;. Finally, mechanisms that include triggering autocrine or paracrine release of growth factors such as TGF-β by mechanical loads to regulate the transcription of "mechanoresponsive genes" are also presented (Davies et al, 1997;Sadoshima and Izumo, 1997). Mechanical stress stimulates the release of TGF-β (Lindahl et al, 2002;Nakatani et al, 2002;Yang et al, 2004) as described in the previous section, as well as enhances its gene transcription through activation of EGR-1 .…”

Cell cultures as models of cardiac mechanoelectric feedback

“…The following studies are specifically those that applied stretch or shear stress to cardiac cell monolayers and provide clear evidence that MEF is involved in different signaling pathways in cardiac cell functions and may play an important role in cardiac diseases caused by increased mechanical loading of the ventricular myocardium, such as dilated cardiomyopathy or hypertrophy. For a general review of myocardial stretch effects at the molecular and cellular levels as they relate to hypertrophy in NRVMs, see Sadoshima and Izumo (1997).…”