title: Candesartan abrogates G protein-coupled receptors agonist-induced MAPK activation and cardiac myocyte hypertrophy.
abstract: The renin-angiotensin-aldosterone system (RAAS) has been identified as a major contributor to the development of cardiac hypertrophy and the subsequent transition to heart failure. G protein-coupled receptors agonists such as angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine (PE) have been implicated in hypertrophic responses in ventricular myocytes through the activation of several families of MAP kinases. In this study we examined the effect of candesartan, an Ang II type 1-(AT1)-receptor antagonist, on cardiac hypertrophy by using cultured neonatal rat cardiomyocytes. Stimulation with Ang II (100 nM), ET-1 (100 nM) or PE (1 µM) induced marked increases in [3H]Leucine incorporation (≥ 50%), compatible with enhanced protein synthesis. The addition of candesartan abrogated the increase in [3H]Leucine incorporation in response not only to Ang II but also to ET-1 and PE. To elucidate the mechanisms involved in this antihypertrophic effect of candesartan, we studied the activation of p38-MAPK, extracellular signal-regulated kinases (ERK1/2) and stress-activated protein kinases (SAPKs). Ang II, ET-1 and PE increased the phosphorylation levels of ERK1/2, p54 SAPK and p46SAPK and p38 in a time-dependent manner. This activation was completely blocked in the case of Ang II by pretreatment with candesartan. ET-1-induced activation of ERKs, SAPKs and p38 was also partially, but significantly, reduced by candesartan. PE-induced activation of SAPKs, but not ERKs and p38, was also reduced by candesartan. These results suggest that the hypertrophic response to ET-1 and PE, along with Ang II, is dependent upon a functioning AT1-receptor and may be mediated by AT 1 activation of the MAP kinases.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.lastname: Zhao Bin Kang
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, hajjar@cvrc. mgh.harvard.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Hajjar
keywords: Ang II type 1 receptor blockers; MAP kinases; candesartan; cardiac hypertrophy