Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

Olson, Erik R.; Shamhart, Patricia E.; Naugle, Jennifer E.; Meszaros, J. Gary

doi:10.1161/hypertensionaha.107.098459

Cited by 102 publications

(80 citation statements)

References 38 publications

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“…Several authors have suggested a role for PKC in ERK1/2 activation by GPCR (34,35), although another recent report indicates that inhibition of PKC in adult cardiomyocytes has no effect in ERK1/2 activation by G q -coupled GPCR (36). However, this is the first report to show a direct link between G␣ q and PKC and to establish a role for such association in the stimulation of the ERK5 MAPK cascade by GPCR.…”

Section: Discussionmentioning

confidence: 67%

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

García-Hoz

Sánchez-Fernández

Diaz‐Meco

et al. 2010

Journal of Biological Chemistry

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G q -coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by G q -coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKC), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by G q -coupled GPCR. Stimulation of ERK5 by G q -coupled GPCR is abolished upon pharmacological inhibition of PKC as well as in embryonic fibroblasts obtained from PKC-deficient mice. Both PKC and MEK5 associate to G␣ q upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of G␣ q as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in G q -mediated physiological functions.The activation of the mitogen-activated protein kinase (MAPK) 3 superfamily plays an important role in a wide variety of signaling pathways involved in embryogenesis, cell proliferation, differentiation, migration, apoptosis, and gene expression. The MAPK superfamily includes the well known extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK1-3), and p38 (␣, ␤, ␥, and ␦) families.In addition, ERK3, ERK4, ERK5 (also termed big MAPK1 or BMK1), and ERK7 are other more recently described MAPK family members that display distinct regulatory mechanisms.A plethora of extracellular stimuli have been found to modulate MAPK cascades (1, 2). Although many aspects remain to be detailed, several studies have described the specific mechanisms by which G protein-coupled receptors (GPCR) can activate the main MAPK families (2-4), which can be modulated by different G␣ or ␤␥ subunits, in a stimulus-or context-specific manner (2, 5).The ERK5 MAPK has been reported to be activated by mitogens (EGF, granulocyte-colony-stimulating factor), agonists of GPCR, cytokines (leukemia inhibitory factor, cardiotrophin-1), and stress (6 -8). ERK5 is selectively activated by the upstream kinase MEK5, which in turn is stimulated by MEKK2 and MEKK3, in a process that appears to involve Src tyrosine kinase activation or the scaffolding function of Gab1 or Lck-associated adaptor (LAD) adaptors depending on the stimuli (7, 9). It has also been described that EGF-mediated ERK5 stimulation requires a direct association between PKC and MEK5 (10) through their respective PB1 domains (11), in a process that may involve scaffold proteins such as p62, to which both . However, the mechanisms by which GPCR stimulate ERK5 are largely unknown. It has been reported that ERK5 stimulation can be triggered by GPCR coupled to the G q and G 12/13 families of heterotrime...

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Section: Discussionmentioning

confidence: 67%

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

García-Hoz

Sánchez-Fernández

Diaz‐Meco

et al. 2010

Journal of Biological Chemistry

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“…Consistent with a potential role for this pathway in cardiovascular disease, the same injurious stimuli such as ANG II and smoking, which are well known to trigger fibrosis, can trigger the activation of fibroblasts to a synthetic phenotype resulting in reparative fibrosis (38,56). This process is initiated by TGF-␤, which is typically produced in response to cellular damage and hormones such as ANg II (22,38). TGF-␤, in turn, stimulates the expression of genes that are characteristic of myofibroblasts, including smooth muscle actin, fibronectin, and osteopontin (25).…”

Section: Discussionmentioning

confidence: 78%

“…A heterozygous deletional mutant of ROCK-I (predominantly expressed in the vasculature and heart) is characterized by reduced perivascular fibrosis (43). Consistent with a potential role for this pathway in cardiovascular disease, the same injurious stimuli such as ANG II and smoking, which are well known to trigger fibrosis, can trigger the activation of fibroblasts to a synthetic phenotype resulting in reparative fibrosis (38,56). This process is initiated by TGF-␤, which is typically produced in response to cellular damage and hormones such as ANg II (22,38).…”

Section: Discussionmentioning

confidence: 92%

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Zhao¹,

Yue²,

Xu³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

110

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Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of Ͻ2.5 m (PM2.5) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM 2.5 exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM 2.5 exposure along with increased expression of the guanine exchange factors (GEFs) PDZRhoGEF and p115 RhoGEF in PM 2.5-exposed mice. Parallel with increased RhoA activation, PM 2.5 exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM2.5 potentiates cardiac remodeling in response to ANG II through RhoA/ Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution. hypertension; vasoconstrictors; angiotensin II AMBIENT AIR POLLUTION mediated by fine particulate matter (PM) of Ͻ2.5 m in aerodynamic diameter (PM 2.5 ) has been associated with adverse cardiovascular outcomes (8,31,39,49). One important mechanism is the elevation in blood pressure (BP) that may occur within hours to days after exposure to high concentrations of PM 2.5 (6,16,21,52). Recent studies (21, 58) have shown that commonly encountered levels of airborne pollutants can result in a prohypertensive response in humans that may be exaggerated in predisposed individuals. This potentiating effect of inhaled particulates has been noted with other chronic conditions or risk factors such as atherosclerosis, diabetes, and postmenopausal status (31,40,49). Although the precise mechanisms remain elusive, there is increasing evidence that PM 2.5 exposure results in rapid changes in the vasculature (7, 32). We (51) have previously shown that PM 2.5 exposure results in the activation of RhoA/Rho-kinase (ROCK) through ROS pathways and hypothesized that this important signaling cascade may mediate at least some of the prohypertensive effects of PM 2.5 . Given the important role of RhoA/ ROCK in a multitude of processes, including the regulation of smooth muscle tone, cellular migration, and hypertrophy (36,47), in the present study we examined the effect of PM 2.5 exposure on vascular function and cardiac remodeling and tested the effects of ROCK antagonism.

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“…44,82 However, Ang II induced proliferation of cardiac fibroblasts through ERK1/2 cascade. [83][84][85] This prompted us to evaluate the activation of the ERK pathway in renal fibroblasts and its dependence on TRPC3; TRPC3 blockade resulted in ERK1/2 phosphorylation inhibition, which was further validated by selective ERK1/2 inhibition resulting in decreased cell proliferation. TRPC3-mediated activation of ERK1/2 was dependent on Ca…”

Section: Discussionmentioning

confidence: 99%

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Saliba¹,

Karam²,

Smayra

et al. 2015

Journal of the American Society of Nephrology

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Transient receptor potential canonical (TRPC) Ca 2+ -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II-and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca 2+ entry in these cells, which was detected by fura-2 Ca 2+ imaging. TRPC3 blockade or Ca 2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signalregulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca 2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca 2+ -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

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Angiotensin II-Induced Extracellular Signal-Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase Cδ and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

Cited by 102 publications

References 38 publications

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

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