Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro

Abstract

Hypertrophy is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle in response to mechanical load. How muscle cells convert mechanical stimuli into growth signals has been a long-standing question. Using an in vitro model of load (stretch)-induced cardiac hypertrophy, we demonstrate that mechanical stretch causes release of angiotensin II (Ang II) from cardiac myocytes and that Ang II acts as an initial mediator of the stretch-induced hypertrophic response. The results not only provide direct evidence for the autocrine mechanism in load-induced growth of cardiac muscle cells, but also define the pathophysiological role of the local (cardiac) renin-angiotensin system.

Genes and the ageing muscle: a review on genetic association studies

“…The D and I alleles are usually associated with higher and lower ACE enzyme activity respectively (Danser et al 1995;Tiret et al 1992;Williams et al 2005). The primary role of ACE in the renin-angiotensin system is to convert angiotensin I into angiotensin II (Rigat et al 1990), which not only acts as a vasoconstrictor but also regulates smooth (Berk et al 1989;Geisterfer et al 1988) and cardiac muscle growth (Sadoshima et al 1993;Ishigai et al 1997). ACE inhibitors have been shown to inhibit hypertrophy in overloaded muscle, which also suggests a role for angiotensin II in skeletal muscle hypertrophy (Gordon et al 2001;Westerkamp and Gordon 2005).…”

Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress

“…In fact, the recent in vitro study has shown that mechanical stretch induces secretion of Ang II from cardiac myocytes of neonatal rats. 16 With regard to the molecular mechanisms by which external load evokes cardiac hypertrophy, protein kinase cascades are the focus of much attention. 17 Some groups, including ours, have shown that the mechanical stretch of neonatal rat cardiomyocytes activates second messengers, such as phosphatidylinositol, protein kinase C (PKC), Raf-1 kinase, and MAP kinase, which are involved in the re-expression of a number of genes, including atrial natriuretic peptide, skeletal ␣ actin, and ␤ MHC followed by an increase in protein synthesis.…”

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

“…28 An increase in angiotensinogen mRNA, angiotensin II release and an upregulation of the number of angiotensin receptors is seen during this response suggesting that the local renin-angiotensin system does play a role in the response to mechanical stimuli. 6 Consistent with this hypothesis angiotensin AT 1 receptor-blockers (whose influence in vivo is described below), partially blunt the myocyte hypertrophic response to mechanical stretch when added to the neonatal cell cultures. 28 …”

“…In neonatal cell culture systems, in the absence of serum containing growth factors or hormones, passive mechanical stretch itself results in a cardiomyocyte hypertrophic response. 6 Once again this is reproducible in adult isolated beating heart models, using a LV balloon. 28 An increase in angiotensinogen mRNA, angiotensin II release and an upregulation of the number of angiotensin receptors is seen during this response suggesting that the local renin-angiotensin system does play a role in the response to mechanical stimuli.…”

“…There is however accumulating evidence for the role of neurohumoral mechanisms and in particular angiotensin II as an effector peptide in this adaptive process. 6 If it were possible to demonstrate that angiotensin II is produced in increasing concentrations as a response to haemodynamic load and then acts on specific receptors to stimulate myocardial growth then we would have a target for ACE inhibition in reducing the LV hypertrophic response to aortic stenosis. To some extent this evidence is now available.…”