Rac1 and RhoA differentially regulate angiotensinogen gene expression in stretched cardiac fibroblasts

Verma, Suresh; Lal, Hind; Golden, Honey B.; Gerilechaogetu, Fnu; Smith, Manuela; Guleria, Rakeshwar S.; Foster, Donald M.; Lu, Guangrong; Dostal, David E.

doi:10.1093/cvr/cvq385

Cited by 49 publications

(38 citation statements)

References 41 publications

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“…Haudenschild and colleagues reported that mechanical stimulation activated SOX9 in human chondrocytes and that RhoA signaling plays an important role in that process [30]. The involvement of Rac1 in mechanosensing and signaling transduction in various nonchondrocytic cell types has been demonstrated [32,33]. Further, one study by Qi et al demonstrated that cyclic mechanical strain stimulation induces proliferation of the vascular smooth muscle cells by activation via Rac1 signaling [34].…”

Section: Discussionmentioning

confidence: 99%

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

Liu

Huang

Liang

et al. 2012

Cell Physiol Biochem

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The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress remain a matter of debate. We explored the signal transduction pathways of proliferation and matrix synthesis when chondrocytes were exposed to periodic mechanical stress. We observed that periodic mechanical stress statistically and significantly enhanced the phosphorylation and activation of Rac1 (p<0.05 for each). Pre-treatment with the Rac1 selective inhibitor NSC23766 attenuated periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis (p<0.05 for each) and abrogated ERK1/2 signal activation (p<0.05), but did not block periodic mechanical stressinduced Src and PLCγ1 phosphorylation in this context. In addition, inhibition of Src with its selective inhibitor PP2 and shRNA targeted to Src blocked Rac1 signal activation (p<0.05 for each), but inhibition of the activity of PLCγ1 did not affect the phosphorylation and activation levels of Rac1 under conditions of periodic mechanical stress. The up-regulation of proliferation and matrix synthesis was inhibited in chondrocytes in response to periodic mechanical stress after pretreatment with blocking antibody against integrinβ1 (p<0.05 for each) but not after pretreatment with blocking antibody against integrinβ3. The phosphorylation levels of ERK1/2, Rac1, PLCγ1 and Src, and Rac1 activation level were also reduced when integrinβ1 was blocked in this context (p<0.05 for each). These findings suggest that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis in part by activating the ERK1/2 mitogenic signal through the integrinβ1-Src-PLCγ1/Rac1-ERK1/2 pathway, which links these important signaling molecules into mitogenic cascades.

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Section: Discussionmentioning

confidence: 99%

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

Liu

Huang

Liang

et al. 2012

Cell Physiol Biochem

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“…Equal amounts of protein (20μg) were separated by SDS-PAGE and assessed by western blotting in indicated protein(s). GAPDH was used as a loading control 39 .…”

Section: Methodsmentioning

confidence: 99%

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

et al. 2017

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Background Activated fibroblasts (myofibroblasts; myoFBs) play critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. We have earlier shown that interleukin-10 (IL10) suppresses PO-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits PO-induced homing of BM-FPCs to the heart and their trans-differentiation to myoFBs and thus attenuates cardiac fibrosis. Methods Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction (TAC). To determine the bone marrow origin, chimeric mice were created using eGFP WT mice marrow to the IL10KO mice. For mechanistic studies, fibroblast progenitor cells were isolated from mouse bone marrow. Results Pressure overload enhanced bone marrow fibroblast progenitor cell (BM-FPC) mobilization and homing in IL10KO mice compared to WT mice. Furthermore, WT bone marrow (from eGFP mice) transplantation in BM-depleted IL10KO mice (IL10KO chimeric mice) reduced TAC-induced BM-FPC mobilization compared to IL10KO mice. GFP co-staining with αSMA or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggest that myofibroblasts were derived from bone marrow post-TAC. Finally, WT-BMT in IL10KO mice inhibited TAC-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited TGFβ-induced transdifferentiation and fibrotic signaling in WT BM-FPC in vitro. Furthermore, fibrosis-associated miRNAs expression was highly upregulated in IL10KO-FPCs compared to WT-FPCs. PCR-based selective miRNA analysis revealed that TGFβ-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145 and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on TGFβ-induced fibrotic signaling in BM-FPC. Conclusion Our findings suggest that IL10 inhibits BM-FPC homing and trans-differentiation to myofibroblasts in pressure overloaded myocardium. Mechanistically for the first time we showed that IL10 suppresses Smad-miRNA-21 mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

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“…For example, β1 integrins regulate the expression of the angiotensinogen gene (AGT) in CFs through p38 signaling in response to mechanical stretch. This effect is mediated by activation of Rac1 and inhibition of RhoA, intracellular kinases involved in cytoskeletal organization and contraction (Verma et al, 2011).…”

Section: Mechanosensors Of Stressmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

117

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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Rac1 and RhoA differentially regulate angiotensinogen gene expression in stretched cardiac fibroblasts

Abstract: These results indicate that stretch-induced activation of Rac1 and RhoA differentially regulates Ao gene expression by modulating p38 and JNK activation.

Cited by 49 publications

References 41 publications

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

Periodic Mechanical Stress Activates Integrin�1-Dependent Src-Dependent PLC?1-Independent Rac1 Mitogenic Signal in Rat Chondrocytes through ERK1/2

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

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