JunB Mediates Basal- and TGFβ1-Induced Smooth Muscle Cell Contractility

Ramachandran, Aruna; Gangopadhyay, Samudra S.; Krishnan, Ramaswamy; Ranpura, Sandeep A.; Rajendran, Kavitha; Ram-Mohan, Sumati; Mulone, Michelle; Gong, Edward M.; Adam, Rosalyn M.

doi:10.1371/journal.pone.0053430

Cited by 17 publications

(14 citation statements)

References 34 publications

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“…RhoA is the small GTPase activator of actin stabilizing kinase, ROCK1, which is the calcium independent activator of myosin regulatory light chain [26]. Myosin regulatory light chain stimulates NM IIA activity and promotes actin filament sliding, including ASMA [27]. …”

Section: Discussionmentioning

confidence: 99%

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Ehanire

Ren

Bond³

et al. 2014

J Mol Med

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Hypertrophic scar contraction (HSc) is caused by granulation tissue contraction propagated by myofibroblast and fibroblast migration and contractility. Identifying the stimulants that promote migration and contractility are key to mitigating HSc. AngiotensinII (AngII) promotes migration and contractility of heart, liver, and lung fibroblasts; thus, we investigated the mechanisms of AngII in HSc. Human scar and unwounded dermis were immunostained for AngII receptors AT1-receptor and AT2-receptor, and analyzed for AT1-receptor expression using western blot. In-vitro assays of fibroblast contraction and migration under AngII stimulation were conducted with AT1-receptor, AT2-receptor, p38, JNK, MEK, and ALK5 antagonism. Excisional wounds were created on AT1-receptor KO and WT mice treated with AngII ± Losartan, and ALK5 and JNK inhibitors SB-431542 and SP-600125 respectively. Granulation tissue contraction was quantified and wounds analyzed by immunohistochemistry. AT1-receptor expression was increased in scar, but not unwounded tissue. AngII induced fibroblast contraction and migration through AT1-receptor. Cell migration was inhibited by ALK5 and JNK, but not p38 or MEK blockade. In-vivo experiments determined that absence of AT1-receptor and chemical AT1-receptor antagonism diminished granulation tissue contraction while AngII stimulated wound contraction. AngII granulation tissue contraction was diminished by ALK5 inhibition, but not JNK. AngII, promotes granulation tissue contraction through AT1-receptor and downstream canonical TGFβ signaling pathway; ALK5. Further understanding the pathogenesis of HSc as an integrated signaling mechanism could improve our approach to establishing effective therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Ehanire

Ren

Bond³

et al. 2014

J Mol Med

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“…31 In addition, AP-1 has been implicated in the regulation of smooth muscle contractility through effects on both myosin and the actin cytoskeleton. 32 We found that the activation of c-Jun induced by TGF-b in HTFs was inhibited by ATRA, with this effect also likely contributing to the inhibition by ATRA of HTF contractility.…”

Section: Discussionmentioning

confidence: 63%

Inhibition by All-Trans-Retinoic Acid of Transforming Growth Factor-β–Induced Collagen Gel Contraction Mediated by Human Tenon Fibroblasts

Liu

Kimura

Orita

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…3,36 It has been described that HS intake increases endothelial production of TGF-β1, which can act in a paracrine fashion on the vessel wall participating in VSMCs differentiation toward a contractile phenotype. 18,[37][38][39] Here, we showed that in the vasculature of the sik1 −/− mice the HS intake increased TGF-β1 expression and downstream phospho-SMAD2/3 signaling compared with the wild-type mice, which suggests that the contractile phenotype of VSMCs should be favored in the sik1 −/− mice. Indeed, we found increased expression of contractile genes and of EN1 in the knockout compared with the wild-type mice aortas, only during HS intake.…”

Section: Discussionmentioning

confidence: 63%

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Bertorello

Pires

Igreja

et al. 2015

Circulation Research

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Rationale:In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes.Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1 −/−) and wild-type (sik1 +/+ ) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1 −/− mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1 +/+ mice. During high-salt intake, the sik1 +/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1 −/− mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Bertorello et al SIK1, Hypertension, and Vascular Remodeling 643Elevated arterial blood pressure can occur as a consequence of increased vascular stiffness attributed to both extracellular matrix deposition/remodeling and enhanced contractility/stiffness of VSMCs. [10][11][12][13] Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that mediates extracellular matrix remodeling processes within the vasculature in addition to promote VSMCs differentiation toward a contractile phenotype.14-18 SIK1 participates in a negative feedback mechanism on the TGF-β1 signaling pathway. 19 We have reported that in epithelial cells the loss of SIK1 increased the expression of SNAI2 and TWIST1, known transcription factors involved in fibrosis and extracellular matrix remodeling. Recently, brain SIK1 activity has been shown to be relevant for blood pressure regulation in rodents by regulating sympathetic activity. Higher hypothalamic activity of SIK1 was associated with reduced sympathoexcitatory activity and lower arterial blood pressure in rats after a high-salt diet and intracerebroventricular infusion of Na + . 20Because SIK1 is present in the vasculature and lower SIK1 activity was associated with elevated blood pressure in humans and rodents, we hypothesize that the lack of SIK1 could trigger vascular remodeling processes leading to increased vascular stiffness and consequently to higher blood pressure. Furthermore, these events alone or in combination with other risk factors (high-s...

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JunB Mediates Basal- and TGFβ1-Induced Smooth Muscle Cell Contractility

Cited by 17 publications

References 34 publications

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction

Inhibition by All-Trans-Retinoic Acid of Transforming Growth Factor-β–Induced Collagen Gel Contraction Mediated by Human Tenon Fibroblasts

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

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