MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells

Abstract

Post‐natal growth of cardiac muscle cells occurs by hypertrophy rather than division and is associated with changes in gene expression and muscle fiber morphology. We show here that the protein kinase MEKK1 can induce reporter gene expression from the atrial natriuretic factor (ANF) promoter, a genetic marker that is activated during in vivo hypertrophy. MEKK1 induced both stress‐activated protein kinase (SAPK) and extracellular signal‐regulated protein kinase (ERK) activity; however, while the SAPK cascade stimulated ANF expression, activation of the ERK cascade inhibited expression. C3 transferase, a specific inhibitor of the small GTPase Rho, also inhibited both MEKK‐ and phenylephrine‐induced ANF expression, indicating an additional requirement for Rho‐dependent signals. Microinjection or transfection of C3 transferase into the same cells did not disrupt actin muscle fiber morphology, indicating that Rho‐dependent pathways do not regulate actin morphology in cardiac muscle cells. While active MEKK1 was a potent activator of hypertrophic gene expression, this kinase did not induce actin organization and prevented phenylephrine‐induced organization. These data suggest that multiple signals control hypertrophic phenotypes. Positive and negative signals mediated by parallel MAP kinase cascades interact with Rho‐dependent pathways to regulate hypertrophic gene expression while other signals induce muscle fiber morphology in cardiac muscle cells.

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

“…Isoprenylation is essential for the activation of RhoA and Ras, as well as ERK1/2, in cardiac myocytes. 35 Because inhibition of isoprenylation is one molecular mechanism underlying the pleiotropic effects of statins, 15,16 our findings suggest that the RhoA/Ras-ERK pathway has a role in the aggravation of hypertensive cardiac hypertrophy induced by large BP variability.…”

Activation of c-Jun N-Terminal Kinases and p38-Mitogen-activated Protein Kinases in Human Heart Failure Secondary to Ischaemic Heart Disease

“…9 Transfection of a construct for inhibitory ("dominant-negative") MEKK1 inhibits PE-induced ANF expression, suggesting that the JNK pathway may be necessary for ANF gene upregulation. 52,65 This construct also attenuates the stimulation of c-Jun-transactivating activity by PE, establishing a potential link through MEKK1 and JNKs to transcription. 52 These experiments are not necessarily unequivocal; although MEKK1 may activate the JNK cascade preferentially, it also activates ERKs and p38-MAPK in cultured cardiac myocytes.…”

“…9,52,65 This pattern of gene expression is associated with hypertrophy in the rat. 21 MEKK1 in combination with MKK4 increases the myocyte profile but does not induce the myofibrillar organization that typifies a true hypertrophic response.…”

“…[62][63][64] Indeed, some investigators believe that they may even be inhibitory. 62,64,65 Because GPCR agonists are now known to activate JNKs and p38-MAPKs, the role(s) of these pathways in hypertrophy is under investigation.…”

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

“…In cultured cardiac myocytes, ERKs are activated by hypertrophic stimuli such as angiotensin II (Ang II) [10], phenylephrine [11,12], endothelin 1 [12][13][14] and PMA [13], as well as cellular stresses such as mechanical stretching [15,16] or osmotic shock [17,18]. Although the role of ERKs in phenylephrineinduced cardiac hypertrophy has been studied by several investigators with different methods, reported roles of ERKs in cardiac hypertrophy vary substantially [19][20][21][22][23]. Furthermore, recent evidence indicates that agonists for the G q -coupled receptor activate not only ERKs but also other members of the MAP kinase family, namely JNK and p38 [17,[24][25][26][27][28], and that these MAP kinases are also important in cardiac hypertrophy [25,26,[29][30][31][32] (reviewed in [5]).…”