Su1862 Smooth Muscle Specific Alpha-Actin Plays a Critical Role in the Regulation of Mechanical Stress-Induced Gene Expression in the Colon

Choudhury, Barun K.; Li, Feng; Shi, Xuan-Zheng P.

doi:10.1016/s0016-5085(15)31798-4

Cited by 4 publications

(5 citation statements)

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“…Further immunohistochemical studies showed that the increased COX-2 expression occurs selectively in the SMC, but not in the mucosa, submucosa, or myenteric plexus (Figure 1 ). Interestingly, Choudhury et al found that MT of COX-2 in colonic SMC was blocked by de-polymerization of actin filaments, or by siRNA silence of smooth muscle specific α-actin (Acta2) (Choudhury et al, 2015 ). These results indicate that SMC specific α-actin is critical in MT of COX-2 in the colon.…”

Section: Mechanical Regulation Of Gene Expression In the Gutmentioning

confidence: 99%

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Shi

2017

Front. Physiol.

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Intraluminal contents and their movement along the gastrointestinal tract create shear stress and mechanical stretch on the gut wall. While the shear stress is important in the initiation of immediate physiological responses, the circumferential mechanical stretch, such as that in obstructive bowel disorders, exerts long-lasting impacts on bowel functions by mainly affecting the deeper muscularis externae. Recent studies demonstrate that mechanical stretch alters gene transcription in gut smooth muscle cells (SMC), and the stretch-altered gene expression (mechano-transcription) may play a critical role in pathogenesis of motility dysfunction and abdominal pain in obstruction. Specifically, stretch-induced cyclo-oxygenase-2 and other pro-inflammatory mediators in gut SMC account for impairments of muscle contractility. Mechano-transcription of pain mediators such as nerve growth factor may contribute to visceral hypersensitivity, by sensitizing primary sensory neurons. This review aims to highlight the novel findings of mechano-transcription in the gut, and to discuss the signaling mechanisms and pathophysiological significance of mechano-transcription.

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Section: Mechanical Regulation Of Gene Expression In the Gutmentioning

confidence: 99%

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Shi

2017

Front. Physiol.

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“…Mechano-transcription of COX-2 was also markedly attenuated by siRNA silencing of SMC specific α-actin (Acta2). These data indicate that SMC specific α-actin within an intact actin filament network is essential in the process whereby mechanical stress induces up-regulation of COX-2 in the colon SMC (Choudhury et al, 2015). Furthermore, reported that mechanical stretch potently activates mitogen-activated protein kinase (MAPK) p38 and protein kinase C (PKC), which are crucial intracellular signaling pathways involved in mechano-transcription of COX-2.…”

Section: Mechano-transcription Of Prostaglandin-endoperoxide Synthase-2 (Cox-2) In Gut Smooth Muscle Cellsmentioning

confidence: 84%

“…The underlying mechanisms for selective expression of COX-2 in SMC by mechanical stretch are not yet clear. A study by Choudhury et al (2015) has shown that mechanotranscription of COX-2 in the colon SMC was abrogated by de-polymerization of actin filament network with latrunculin B or swinholide. Mechano-transcription of COX-2 was also markedly attenuated by siRNA silencing of SMC specific α-actin (Acta2).…”

Section: Mechano-transcription Of Prostaglandin-endoperoxide Synthase-2 (Cox-2) In Gut Smooth Muscle Cellsmentioning

confidence: 99%

“…Furthermore, reported that mechanical stretch potently activates mitogen-activated protein kinase (MAPK) p38 and protein kinase C (PKC), which are crucial intracellular signaling pathways involved in mechano-transcription of COX-2. However, treatments with Acta2 siRNA or latrunculin B or swinholide also restricted stretch-induced activation of p38 and PKC (Choudhury et al, 2015). Thus, an integrated smooth muscle actin network is essential for linking the mechanical signal to activation of MAPK and PKC and, thus, for mechano-transcription of COX-2.…”

Section: Mechano-transcription Of Prostaglandin-endoperoxide Synthase-2 (Cox-2) In Gut Smooth Muscle Cellsmentioning

confidence: 99%

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Targeting Mechano-Transcription Process as Therapeutic Intervention in Gastrointestinal Disorders

et al. 2021

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Mechano-transcription is a process whereby mechanical stress alters gene expression. The gastrointestinal (GI) tract is composed of a series of hollow organs, often encountered by transient or persistent mechanical stress. Recent studies have revealed that persistent mechanical stress is present in obstructive, functional, and inflammatory disorders and alters gene transcription in these conditions. Mechano-transcription of inflammatory molecules, pain mediators, pro-fibrotic and growth factors has been shown to play a key role in the development of motility dysfunction, visceral hypersensitivity, inflammation, and fibrosis in the gut. In particular, mechanical stress-induced cyclooxygenase-2 (COX-2) and certain pro-inflammatory mediators in gut smooth muscle cells are responsible for motility dysfunction and inflammatory process. Mechano-transcription of pain mediators such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) may lead to visceral hypersensitivity. Emerging evidence suggests that mechanical stress in the gut also leads to up-regulation of certain proliferative and pro-fibrotic mediators such as connective tissue growth factor (CTGF) and osteopontin (OPN), which may contribute to fibrostenotic Crohn’s disease. In this review, we will discuss the pathophysiological significance of mechanical stress-induced expression of pro-inflammatory molecules, pain mediators, pro-fibrotic and growth factors in obstructive, inflammatory, and functional bowel disorders. We will also evaluate potential therapeutic targets of mechano-transcription process for the management of these disorders.

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“…Thus, mechano-transcription of COX-2 in BO is a smooth muscle specific phenomenon. Choudhury et al (2015) found that SMC specific α-actin with an intact intracellular network is required for mechano-transcription of COX-2 in colonic SMC. Li et al (2012a) further studied the intracellular mechanisms of mechano-transcription of COX-2 in gut SMC, and found that mitogen-activated protein kinase (MAPK) ERK, p38, and JNK, and protein kinase C (PKC) especially PKCdelta, are important parts of signaling cascade in mechano-transcription of COX-2 ( Li et al, 2012a , b ; Shi, 2017 ).…”

Section: Mechanical Stretch-induced Gene Expression Of Pain Mediatorsmentioning

confidence: 94%

Novel Insights Into the Mechanisms of Abdominal Pain in Obstructive Bowel Disorders

Shi

Lin

Hegde

2018

Front. Integr. Neurosci.

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Obstructive bowel disorders (OBD) are characterized by lumen distention due to mechanical or functional obstruction in the gut. Abdominal pain is one of the main symptoms in OBD. In this article, we aim to critically review the potential mechanisms for acute and chronic pain in bowel obstruction (BO). While clustered contractions and associated increase of intraluminal pressure may account for colicky pain in simple obstruction, ischemia may be involved in acute pain in severe conditions such as closed loop obstruction. Recent preclinical studies discovered that visceral sensitivity is increased in BO, and visceral hypersensitivity may underlie the mechanisms of chronic abdominal pain in BO. Mounting evidence suggests that lumen distension, as a circumferential mechanical stretch, alters gene expression (mechano-transcription) in the distended bowel, and mechano-transcription of nociceptive and inflammatory mediators plays a critical role in the development of visceral hypersensitivity in BO. Mechano-transcription of nerve growth factor (NGF) in gut smooth muscle cells is found to increase voltage-gated Na+ channel (Nav) activity of the primary sensory neurons by up-regulating expression of TTX-resistant Nav1.8, whereas mechanical stretch-induced brain-derived neurotrophic factor (BDNF) reduces Kv currents especially A-type (IA) currents by down-regulating expression of specific IA subtypes such as Kv1.4. The NGF and BDNF mediated changes in gene expression and channel functions in the primary sensory neurons may constitute the main mechanisms of visceral hypersensitivity in OBD. In addition, mechanical stretch-induced COX-2 and other inflammatory mediators in the gut may also contribute to abdominal pain by activating and sensitizing nociceptors.

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Su1862 Smooth Muscle Specific Alpha-Actin Plays a Critical Role in the Regulation of Mechanical Stress-Induced Gene Expression in the Colon

Cited by 4 publications

References 0 publications

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Mechanical Regulation of Gene Expression in Gut Smooth Muscle Cells

Targeting Mechano-Transcription Process as Therapeutic Intervention in Gastrointestinal Disorders

Novel Insights Into the Mechanisms of Abdominal Pain in Obstructive Bowel Disorders

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