Investigation of the inhibitory effects of HA‐1077 and Y‐32885 on the translocation of PKCβI, PKCβII and PKCζ in human neutrophils

Siomboing, Xavier; Gressier, Bernard; Dine, T.; Brunet, C.; Luyckx, M.; Cazin, Michelene; Cazin, Jean‐Claude

doi:10.1080/09629350120102334

Cited by 4 publications

(4 citation statements)

References 33 publications

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“…3) and IL‐6 promoter expression, suggesting a role of this downstream kinase in both effects. The effect on PKC in the UMR‐106 cells is consistent with a previous report showing that Rho kinase inhibition decreases PKC translocation in human polymorphonuclear neutrophils (41) …”

Section: Discussionsupporting

confidence: 91%

Rho and Rho Kinase Are Involved in Parathyroid Hormone-Stimulated Protein Kinase C α Translocation and IL-6 Promoter Activity in Osteoblastic Cells

Radeff

Nagy

Stern

2004

Journal of Bone and Mineral Research

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Inhibition of Rho proteins with Clostridium difficile toxin B or inhibition of Rho prenylation with GGTI attenuated PTH(1-34)- and PTH(3-34)-stimulated translocation of endogenous PKCalpha and IL-6 promoter activity. Expression of a constitutively active RhoA (RhoA63L) mimicked the effect of PTH(1-34) or PTH(3-34) to promote membrane localization of PKCalpha, whereas cells expressing a dominant negative RhoA (RhoA19N) did not respond to PTH(1-34) or PTH(3-34). The Rho kinase inhibitor Y27632 attenuated PTH(1-34)- and PTH(3-34)-stimulated PKCalpha translocation and IL-6 promoter activation. Rho seemed to be acting at a step before production of diacylglycerol (DAG), because the stimulation of PKCalpha translocation by the DAG mimetic phorbol 12,13 dibutyrate (PDBu) was unaffected by C. difficile toxin B or Y27632. These results indicate that Rho proteins are an important component of PTH signaling in osteoblastic cells and provide further demonstration of convergence between PKC and small G-protein signaling pathways.

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Section: Discussionsupporting

confidence: 91%

Rho and Rho Kinase Are Involved in Parathyroid Hormone-Stimulated Protein Kinase C α Translocation and IL-6 Promoter Activity in Osteoblastic Cells

Radeff

Nagy

Stern

2004

Journal of Bone and Mineral Research

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“…Additionally, almost any drug that alters Rho/ROCK will also simultaneously affect BP. An additional limitation pertains to the use of pharmacological inhibitors of the ROCK pathway as these inhibitors may have nonspecific effects through targeting of other kinases, including PKC (48). Thus, some of our effects may relate to non-ROCK effects of fasudil.…”

Section: Discussionmentioning

confidence: 99%

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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“…Previous studies demonstrated that RhoA/ROCKs/MRTF-A signaling contributes to pathological cardiac hypertrophy by promoting serum response factor (SRF)-dependent fetal gene expression. 15,17–19 Then, SRF response element reporter luciferase assays were performed in NRVMs with either decreased or increased levels of PDZ-RhoGEF. As shown in Figure S4G, Ang II-induced SRF-dependent transcription was significantly limited by PDZ-RhoGEF deficiency but was further enhanced in PDZ-RhoGEF-overexpressing NRVMs.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we presume that PDZ-RhoGEF links Gα12/13-coupled GPCRs to RhoA/ ROCKs signaling upon Ang II treatment and that activated RhoA/ROCKs signaling in turn promotes PDZ-RhoGEF expression to further augment the activated signals, forming a positive feedback mechanism. However, since the use of pharmacological inhibitors of the ROCKs pathway in this study, some of the effects of fasudil on PDZ-RhoGEF expression may be related to nonspecific effects through targeting other kinases, such as protein kinase C. 10,19 Furthermore, the expression of PDZ-RhoGEF may be dynamically regulated by complex molecular networks during the progression of pathological cardiac hypertrophy. Initially, signaling pathways, including RhoA, may contribute to PDZ-RhoGEF upregulation in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 96%

Detrimental Role of PDZ-RhoGEF in Pathological Cardiac Hypertrophy

Huang

Dai

et al. 2023

Hypertension

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BACKGROUND: Postsynaptic density 95/disk-large/ZO-1 Rho guanine nucleotide exchange factor (PDZ-RhoGEF, PRG) functions as a RhoGEF for activated Gα13 and transmits activation signals to downstream signaling pathways in various pathological processes. Although the prohypertrophic effect of activated Gα13 (a heterotrimeric G protein) is well-established, the role of PDZ-RhoGEF in pathological cardiac hypertrophy is still obscure. METHODS: Genetically engineered mice and neonatal rat ventricular myocytes were generated to investigate the function of PRG in pathological myocardial hypertrophy. The prohypertrophic stimuli-induced alternations in the morphology and intracellular signaling were measured in myocardium and neonatal rat ventricular myocytes. Furthermore, multiple molecular methodologies were used to identify the precise molecular mechanisms underlying PDZ-RhoGEF function. RESULTS: Increased PDZ-RhoGEF expression was documented in both hypertrophied hearts and neonatal rat ventricular myocytes. Upon prohypertrophic stimuli, the PDZ-RhoGEF-deficient hearts displayed alleviated cardiomyocyte enlargement and attenuated collagen deposition with improved cardiac function, whereas the adverse hypertrophic responses in hearts and neonatal rat ventricular myocytes were markedly exaggerated by PDZ-RhoGEF overexpression. Mechanistically, RhoA-dependent signaling pathways may function as the downstream effectors of PDZ-RhoGEF in hypertrophic remodeling, as confirmed by rescue experiments using a RhoA inhibitor and dominant-negative RhoA. Furthermore, PDZ-RhoGEF is associated with activated Gα13 and contributes to Gα13-mediated activation of RhoA-dependent signaling. CONCLUSIONS: Our data provide the first evidence that PDZ-RhoGEF promotes pathological cardiac hypertrophy by linking activated Gα13 to RhoA-dependent signaling pathways. Therefore, PDZ-RhoGEF has the potential to be a diagnostic marker or therapeutic target for pathological cardiac hypertrophy.

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Investigation of the inhibitory effects of HA‐1077 and Y‐32885 on the translocation of PKCβI, PKCβII and PKCζ in human neutrophils

Cited by 4 publications

References 33 publications

Rho and Rho Kinase Are Involved in Parathyroid Hormone-Stimulated Protein Kinase C α Translocation and IL-6 Promoter Activity in Osteoblastic Cells

Rho and Rho Kinase Are Involved in Parathyroid Hormone-Stimulated Protein Kinase C α Translocation and IL-6 Promoter Activity in Osteoblastic Cells

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

Detrimental Role of PDZ-RhoGEF in Pathological Cardiac Hypertrophy

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