scholarly journals Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway

2018 ◽  
Vol 51 (2) ◽  
pp. 842-853 ◽  
Author(s):  
Yongshun Wang ◽  
Wei Cao ◽  
Jinjin Cui ◽  
Yang Yu ◽  
Yubo Zhao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Hippo Pathway ◽  
Wall Stress ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Phenotypic Switch ◽  
Arterial Smooth Muscle ◽  
Arterial Smooth Muscle Cells ◽  
The Hippo Pathway

Background/Aims: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch-mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined. Methods: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. Results: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. Conclusion: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis.

Abstract 17308: Effect of HIV Protein-Tat & Cocaine on Hippo-YAP Signaling Axis in Pulmonary Arterial Smooth Muscle Cells

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Aradhana Mohan ◽  
Himanshu Sharma ◽  
Mahendran Chinnappan ◽  
Navneet K Dhillon
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Hippo Pathway ◽  
Combined Treatment ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Hiv Tat ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Introduction and hypothesis: Intravenous drug use (IVDU) is considered to be one of the important risk factors in the development of HIV-associated pulmonary arterial hypertension (HPAH). Our previous findings demonstrate that the exposure of cocaine to HIV infected individuals has an additive effect in enhancing the proliferation of pulmonary smooth muscle cells, thus further amplifying the development of pulmonary arteriopathy. Furthermore, various studies suggest the failure of Hippo pathway and increased YAP/TAZ activity in pulmonary hypertension (PH). Based on this, we hypothesized that YAP axis might be having a role in HIV and cocaine mediated smooth muscle hyperplasia. Methods: Primary human pulmonary arterial smooth muscle cells (HPASMCs) were grown and treated with cocaine hydrochloride (1μM) and/or HIV-Tat protein (25ng/mL) for 6h. In addition, primary HPASMC were treated for 24h with extracellular vesicles (EVs) transfected with miR-130a antagomir or scrambled miR followed by treatment of EVs isolated from supernatants of monocyte derived macrophage infected with HIV-Bal (5ng/ml) in the presence or absence of cocaine for 4 days. The expression of Hippo proteins was determined using western blot. Results: Combined treatment of HPASMCs with HIV-Tat and cocaine for 6h showed no change in the expression of MST proteins, however reduced expression of phosphorylated LATS1 relative to total LATS1 was observed. This correlated with the decline in the phosphorylated YAP to total YAP ratio. Pre-treatment of HPASMCs with YAP/TAZ inhibitor attenuated the HIV-Tat and cocaine mediated augmentation of cell proliferation. Furthermore, our recent findings demonstrate that EVs derived from HIV infected and cocaine treated MDMs (H+C EVs) when added to HPASMC result in increased proliferation on transfer of miR-130a. We now found that this H+C EVs mediated hyper-proliferation of smooth muscle cells is associated with the increased levels of total YAP protein. In addition, H+C EVs mediated increase in total YAP was prevented on the pretreatment of HPASMCs with EVs carrying anti-miR-130a. Conclusion: In conclusion, our preliminary findings suggest increased activation of Hippo-YAP signaling in pulmonary smooth muscle cells on the direct treatment with HIV protein and cocaine and also on exposure to EVs derived from HIV infected and cocaine treated macrophages.

scholarly journals Contribution of Nrf2 to Atherogenic Phenotype Switching of Coronary Arterial Smooth Muscle Cells Lacking CD38 Gene

2015 ◽  
Vol 37 (2) ◽  
pp. 432-444 ◽  
Author(s):  
Ming Xu ◽  
Xiao-Xue Li ◽  
Lei Wang ◽  
Mi Wang ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Gene Silencing ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Phenotypic Change ◽  
Arterial Smooth Muscle ◽  
Arterial Smooth Muscle Cells ◽  
O2 Production ◽  
Expression And Activity

Background/Aims: Recent studies have indicated that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle cells upon atherogenic stimulations. However, the molecular mechanisms mediating this vascular smooth muscle (SMC) phenotypic switching remain unknown. Methods & Results: In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38-/- mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin, SM22α and α-SMA but increased the expression of SMC dedifferentiation marker, vimentin, which was accompanied by enhanced cell proliferation. This phenotypic change in CD38-/- CAMs was enhanced by 7-ketocholesterol (7-Ket), an atherogenic stimulus. We further found that the CD38 deficiency decreased the expression and activity of nuclear factor E2-related factor 2 (Nrf2), a basic leucine zipper (bZIP) transcription factor sensitive to redox regulation. Similar to CD38 deletion, Nrf2 gene silencing increased CAM dedifferentiation upon 7-Ket stimulation. In contrast, the overexpression of Nrf2 gene abolished 7-Ket-induced dedifferentiation in CD38-/- CAMs. Given the sensitivity of Nrf2 to oxidative stress, we determined the role of redox signaling in the regulation of Nrf2 expression and activity associated with CD38 effect in CAM phenotype changes. It was demonstrated that in CD38-/- CAMs, 7-Ket failed to stimulate the production of O2-., while in CD38+/+ CAMs 7-Ket induced marked O2-. production and enhancement of Nrf2 activity, which was substantially attenuated by NOX4 gene silencing. Finally, we demonstrated that 7-Ket-induced and NOX4-dependent O2-. production was inhibited by 8-Br-cADPR, an antagonist of cADPR or NED-19, an antagonist of NAADP as product of CD38 ADP-ribosylcyclase, which significantly inhibited the level of cytosolic Ca2+ and the activation of Nrf2 under 7-Ket. Conclusion: Taken together, these results suggest that CD38 activity is required for 7-Ket-induced Ca2+ and consequently O2-. production in CAMs, which increases Nrf2 activity to maintain their differentiated status. When CD38 gene expression and function are deficient, the Nrf2 activity is suppressed, thereby leading to phenotypic switching of CAMs.

scholarly journals Effects of vasopressin on ATP-sensitive and Ca2+-activated K+ channels of coronary arterial smooth muscle cells

1992 ◽  
Vol 58 ◽  
pp. 339
Author(s):  
Tetsuzo Wakatsuki ◽  
Yutaka Nakaya ◽  
Yukiko Miyoshi ◽  
Zeng Xiao-Rong ◽  
Masahiro Nomura ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
K Channels ◽  
Arterial Smooth Muscle Cells

Propagation of fast and slow intercellular Ca2+ waves in primary cultured arterial smooth muscle cells

Cell Calcium ◽  
2011 ◽  
Vol 50 (5) ◽  
pp. 459-467 ◽  
Author(s):  
Nadia Halidi ◽  
François-Xavier Boittin ◽  
Jean-Louis Bény ◽  
Jean-Jacques Meister
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Arterial Smooth Muscle ◽  
Arterial Smooth Muscle Cells
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