Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro

Abstract

Although MAP (mitogen-activated protein) kinases are implicated in cell proliferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared with phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenylephrine caused stronger and more sustained activation of JNK and p38 than Ang II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK),inhibited Ang II-induced, but not phenylephrine-induced, expression of atrial natriuretic factor (ANF) at both the mRNA and polypeptide levels. SB203580, a specific inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promoter, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Phenylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negative MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-regulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal α-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist-specific and phenotype-specific response in cardiac hypertrophy.

Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction

“…In cardiomyocytes, activation of all three members by Ang II can be blocked by inhibiting superoxide formation (Aoki et al, 2000;Zhang et al, 2004). Our results showed that NO blocked MI-induced JNK activation but had no effect on ERK or p38 MAPK activation (data not shown).…”

Mitogen-activated protein kinases in the heart

“…PD 98059 inhibited the myofibrillar organization (Clerk et al 1998c), ANP expression (Baliga et al 1999;Silberbach et al 1999) and brain natriuretic peptide expression (Liang et al 2000) induced by endothelin-1, α 1 -adrenoceptor agonists, neuregulin-1 and/or mechanical strain in some studies, but in others inhibited the expression of ANP and/or brain natriuretic peptide expression only partially (Kometiani et al 1998) or not at all . Moreover, PD 98059 did not inhibit the increase in skeletal α-actin or the repression of the α3-subunit of Na + /K + -ATPase (Kometiani et al 1998) and caused only small if any inhibition of morphologically determined hypertrophy (Aoki et al 2000;Baliga et al 1999;Choukroun et al 1998;Clerk et al 1998c;Nemoto et al 1998;Silberbach et al 1999). Rather PD 98059 was reported to block the anti-hypertrophic effect of ANP (Silberbach et al 1999).…”

“…While studies on surrogate markers of cardiac hypertrophy induction such as activation of ANP and brain natriuretic peptide promoters have yielded mixed results (Aoki et al 2000;Liang et al 1997;Nemoto et al 1998), direct and indirect evidence support the idea that cardiac hypertrophy development may involve JNK. For example, hypertrophy-promoting stimuli were reported to activate JNK in almost all studies.…”

Activation of mesangial cell MAPK in responseto homocysteine

“…The most studied chemical stimuli in models of progressive glomerular disease are the cytokines such as Ang II [8] and TGF-b [57]. Ang II signaling in VSMC results in proliferation and matrix production, and these effects are also dependent on Erk signaling [58,59]. Inhibition of Erk attenuates responsiveness of VSMC to Ang II, further implicating this signaling pathway [60].…”