Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

Li, Hongliang; He, Chengwei; Feng, Jinhua; Zhang, Yan; Tang, Qi‐Zhu; Bian, Zhou‐Yan; Bai, Xue; Zhou, Haoming; Jiang, Hong; Heximer, Scott P.; Qin, Mu; Huang, He; Liu, Peter P.; Huang, Congxin

doi:10.1073/pnas.1008397107

Cited by 119 publications

(129 citation statements)

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“…6A). The increased basal protein phosphorylation in RGS5-depleted cells is concordant with previous studies (28,37). Consistent with the function of RGS5 as an upstream negative regulator at the level of G protein activation, phosphorylation of other GPCR-activated kinases (Erk and Akt) was also increased in cells expressing RGS5 siRNA compared with control (Fig.…”

Section: ␤-Agonist Regulation Of Bronchial Rgs5 Expressionsupporting

confidence: 80%

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Yang

Cooper

Damera

et al. 2011

Journal of Biological Chemistry

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Although short-acting and long-acting inhaled ␤ 2 -adrenergic receptor agonists (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone without concomitant anti-inflammatory drugs (corticosteroids) may increase the risk of disease exacerbation in some patients. We found previously that pretreatment of human precision-cut lung slices (PCLS) with SABA impaired subsequent ␤ 2 -agonistinduced bronchodilation, which occurred independently of changes in receptor quantities. Here we provide evidence that prolonged exposure of cultured human airway smooth muscle (HuASM) cells to ␤ 2 -agonists directly augments procontractile signaling pathways elicited by several compounds including thrombin, bradykinin, and histamine. Such treatment did not increase surface receptor amounts or expression of G proteins and downstream effectors (phospholipase C␤ and myosin light chain). In contrast, ␤-agonists decreased expression of regulator of G protein signaling 5 (RGS5), which is an inhibitor of G-protein-coupled receptor (GPCR) activity. RGS5 knockdown in HuASM increased agonistevoked intracellular calcium flux and myosin light chain (MLC) phosphorylation, which are prerequisites for contraction. PCLS from Rgs5 ؊/؊ mice contracted more to carbachol than those from WT mice, indicating that RGS5 negatively regulates bronchial smooth muscle contraction. Repetitive ␤ 2 -agonist use may not only lead to reduced bronchoprotection but also to sensitization of excitation-contraction signaling pathways as a result of reduced RGS5 expression.Asthma is a complex disorder of unknown etiology characterized by increased bronchial smooth muscle contraction, lung inflammation, and tissue remodeling. These and other abnormalities reduce airway luminal diameter and increase stiffness. A cardinal feature of asthma is "airway hyper-responsiveness" (AHR), 2 which refers to the increased bronchial contraction to inhaled procontractile agonists such as methacholine that is observed in asthmatics relative to healthy controls. AHR manifests as reduced airflow (1-4). In allergic asthma, mediators secreted by activated inflammatory leukocytes or resident lung cells including histamine, leukotrienes, bradykinin, and thrombin promote ASM contraction by activating GPCRs linked to activation (GTP binding) of G␣ q (5). This initiates a signaling route culminating in generation of inositol (3, 4, 5)-trisphosphate and release of Ca 2ϩ from endoplasmic reticulum by activation of IP3 receptors. Hydrolysis of GTP by G␣ q promotes pathway deactivation through formation of inactive G␣ q -GDP-G␤␥ heterotrimers. G␣ q signaling is required for AHR in mouse models of allergic airway inflammation (6).Receptor-related events increase the frequency of intracellular Ca 2ϩ oscillations in ASM, which induces Ca 2ϩ -calmodulindependent protein kinase (CaMK)-mediated activation of myosin light chain kinase (MLCK). Phosphorylation of myosin light chain (MLC) on Ser-19 by MLCK promotes actin-myosin filament interactions and muscle fiber shortening through the...

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Section: ␤-Agonist Regulation Of Bronchial Rgs5 Expressionsupporting

confidence: 80%

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Yang

Cooper

Damera

et al. 2011

Journal of Biological Chemistry

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“…[1][2][3] Although cardiac hypertrophy might initially represent an adaptive response of the myocardium, it frequently progresses to ventricular dilatation and heart failure. Heart failure is a debilitating disease with high morbidity and mortality rates, and its prevalence is increasing.…”

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confidence: 99%

Novel Role for Caspase-Activated DNase in the Regulation of Pathological Cardiac Hypertrophy

et al. 2015

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Abstract-Caspase-activated DNase (CAD) is a double-strand-specific endonuclease that is responsible for the cleavage of nucleosomal spacer regions and subsequent chromatin condensation during apoptosis. Given that several endonucleases (eg, DNase I, DNase II, and Endog) have been shown to regulate pathological cardiac hypertrophy, we questioned whether CAD, which is critical for the induction of DNA fragmentation, plays a pivotal role in pressure overload-elicited cardiac hypertrophy. A CAD-knockout mouse model was generated and subjected to aortic banding for 8 weeks. The extent of cardiac hypertrophy was evaluated by echocardiography and pathological and molecular analyses. Our results demonstrated that the disruption of CAD attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, transgenic mice with cardiac-specific overexpression of CAD showed an aggravated cardiac hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 was significantly reduced in the CADknockout hearts compared with the control hearts; however, they were greatly increased in the CAD-overexpressing hearts after aortic banding. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes after treatment with angiotensin II for 48 hours. These data indicate that CAD functions as a necessary modulator of the hypertrophic response by regulating the mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 signaling pathway in the heart. Our study suggests that CAD might be a novel target for the treatment of pathological cardiac hypertrophy and heart failure. (Hypertension. 2015;65:871-881.

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“…Constitutively, ERK1/2 activation could promote physiological cardiac hypertrophy in vivo under normal condition. 48 Under pathological circumstances, direct inhibition of MEK-ERK1/2 signaling did improve pressure overload-induced pathological cardiac hypertrophy, 43,49 as evidenced by our current study using U0126. Moreover, the study using ERK1/2-KO mice identified that ERK1/2 might be a necessary component to drive hypertrophic response with cell widening under hypertrophic stimuli.…”

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confidence: 73%

“…[42][43][44] About the function of RGS10 in the heart, whether RGS10 serves as a component that inhibits the development of cardiac hypertrophy or exhibits unanticipated influence, remains unknown. The present study demonstrated that RGS10 exhibited a significant improvement in pathological cardiac hypertrophy, and we think that RGS10 and B/R4 members work collaboratively under this situation.…”

mentioning

confidence: 99%

Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

Miao

Xing

et al. 2016

Hypertension

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Regulator of G-protein signaling 10 (RGS10) is an important member of the RGS family and produces biological effects in multiple organs. We used a genetic approach to study the role of RGS10 in the regulation of pathological cardiac hypertrophy and found that RGS10 can negatively influence pressure overload–induced cardiac remodeling. RGS10 expression was markedly decreased in failing human hearts and hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in RGS10-knockout mice was exacerbated, whereas the heart of transgenic mice with cardiac-specific RGS10 overexpression exhibited an alleviated response to pressure overload. Consistently, RGS10 also inhibited an angiotensin II–induced hypertrophic response in isolated cardiomyocytes. Mechanistically, cardiac remodeling improvement elicited by RGS10 was associated with the abrogation of mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated protein kinase 1/2 signaling. Furthermore, the inhibition of mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 transduction abolished RGS10 deletion-induced hypertrophic aggravation. These findings place RGS10 and its downstream signaling mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2 as crucial regulators of pathological cardiac hypertrophy after pressure overload and identify this pathway as a potential therapeutic target to attenuate the pressure overload–driven cardiac remodeling.

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Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

Cited by 119 publications

References 20 publications

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Novel Role for Caspase-Activated DNase in the Regulation of Pathological Cardiac Hypertrophy

Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase–Extracellular Signal-Regulated Protein Kinase 1/2 Signaling

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