scholarly journals Abnormal TPM2 expression is involved in the regulation of atherosclerosis progression via mediating RhoA signaling in vitro

2021 ◽  
Author(s):  
Jimei zhang ◽  
Chonghong Zhang ◽  
Li Miao ◽  
Zimin Meng ◽  
Ning Gu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Injury ◽  
Critical Role ◽  
Regulation Mechanism ◽  
Growth Depression ◽  
Atherosclerosis Progression ◽  
Cellular Processes ◽  
Vitro Model

IntroductionOx-LDL (oxidized low densitylipoprotein)-induced endothelial cell injury and dysfunction of vascular smooth muscle cell played critical roles in the development of atherosclerosis (AS). Tropomyosin 2 (TPM2) was indicated to be implicated in cardiac diseases, but its critical role and regulation mechanism in AS progression had not yet been elucidated.Material and methodsThe expression of TPM2 was investigated in AS tissues. Ox-LDL was used to construct an AS in vitro model based on endothelial and vascular smooth muscle cells (HAEC and VSMC). Overexpression assay was performed to evaluate the role of TPM2 in AS. Meanwhile, Narciclasine treatment analysed the involvement of RhoA pathway.ResultsTPM2 was dramatically upregulated both in AS tissues and ox-LDL-induced HAEC cells. The overexpression of TPM2 attenuated ox-LDL-stimulated cell growth depression, inflammatory and adhesive responses in HAEC, as well as oxidative stress and mitochondrial dysfunction. Besides, VSMC, impacted by TPM2-overexpressed HAEC, showed alleviated cellular processes which was abnormally activation induced by ox-LDL. Furthermore, the depressed activation of RhoA pathway was found in TPM2-overexpressed HAEC and activating the signaling rescued these effects of TPM2 exerted on ox-LDL-stimulated HAEC and VSMC.ConclusionsTPM2 had an advantageous impact on ox-LDL-induced AS progression in vitro via mediating RhoA pathway. This evidence might be contributed to the therapy of AS.

scholarly journals TRPV1 in arteries enables a rapid myogenic tone

2021 ◽  
Author(s):  
Thieu X Phan ◽  
Hoai T Ton ◽  
Hajnalka Gulyas ◽  
Robert Porszasz ◽  
Attila Toth ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Critical Role ◽  
Myogenic Tone ◽  
Dynamic Regulation ◽  
Membrane Stretch

Arterioles maintain blow flow by adjusting their diameter in response to changes in local blood pressure. In this process called the myogenic response, a vascular smooth muscle mechanosensor controls tone predominantly through altering the membrane potential. In general, myogenic responses occur slowly, reaching a plateau in minutes. In the heart and skeletal muscle, however, myogenic tone is rapid; activation occurs in tens of seconds and arterial constrictions or raised extravascular pressure as brief as 100 ms remove tone. Previously, we identified extensive expression of TRPV1 in the smooth muscle of arterioles supplying skeletal muscle, heart and the adipose. Here, we reveal a critical role for TRPV1 in the myogenic tone of these tissues. TRPV1 antagonists dilated skeletal muscle arterioles in vitro and in vivo , increased coronary flow in isolated hearts, and transiently decreased blood pressure. All of these effects of TRPV1 antagonists were abolished by genetic disruption of TRPV1. Stretch of isolated vascular smooth muscle cells, or raised intravascular pressure in arteries (with or without endothelium), triggered Ca2+ signaling and vasoconstriction. The majority of these stretch-responses were TRPV1-mediated, with the remaining tone being inhibited by the TRPM4 antagonist, 9-phenantrol. Notably, tone developed more quickly in arteries from wild-type compared with TRPV1-null mice. Furthermore, the rapid vasodilation following brief constriction of arterioles was also dependent on TRPV1, consistent with a rapid deactivation or inactivation of TRPV1. Pharmacologic experiments revealed that membrane stretch activates a phospholipase C/protein kinase C signaling pathway to activate TRPV1, and in turn, L-type Ca2+ channels. These results suggest a critical role, for TRPV1 in the dynamic regulation of myogenic tone and blood flow in the heart and skeletal muscle.

scholarly journals Salt-Inducible Kinase 3 Promotes Vascular Smooth Muscle Cell Proliferation and Arterial Restenosis by Regulating AKT and PKA-CREB Signaling

2021 ◽  
Author(s):  
Yujun Cai ◽  
Xue-Lin Wang ◽  
Jinny Lu ◽  
Xin Lin ◽  
Jonathan Dong ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Actin Polymerization ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Neointima Formation ◽  
Arterial Restenosis

Objective: Arterial restenosis is the pathological narrowing of arteries after endovascular procedures, and it is an adverse event that causes patients to experience recurrent occlusive symptoms. Following angioplasty, vascular smooth muscle cells (SMCs) change their phenotype, migrate, and proliferate, resulting in neointima formation, a hallmark of arterial restenosis. SIKs (salt-inducible kinases) are a subfamily of the AMP-activated protein kinase family that play a critical role in metabolic diseases including hepatic lipogenesis and glucose metabolism. Their role in vascular pathological remodeling, however, has not been explored. In this study, we aimed to understand the role and regulation of SIK3 in vascular SMC migration, proliferation, and neointima formation. Approach and Results: We observed that SIK3 expression was low in contractile aortic SMCs but high in proliferating SMCs. It was also highly induced by growth medium in vitro and in neointimal lesions in vivo. Inactivation of SIKs significantly attenuated vascular SMC proliferation and up-regulated p21 CIP1 and p27 KIP1 . SIK inhibition also suppressed SMC migration and modulated actin polymerization. Importantly, we found that inhibition of SIKs reduced neointima formation and vascular inflammation in a femoral artery wire injury model. In mechanistic studies, we demonstrated that inactivation of SIKs mainly suppressed SMC proliferation by down-regulating AKT (protein kinase B) and PKA (protein kinase A)-CREB (cAMP response element-binding protein) signaling. CRTC3 signaling likely contributed to SIK inactivation-mediated antiproliferative effects. Conclusions: These findings suggest that SIK3 may play a critical role in regulating SMC proliferation, migration, and arterial restenosis. This study provides insights into SIK inhibition as a potential therapeutic strategy for treating restenosis in patients with PAD.

scholarly journals Globular adiponectin inhibits osteoblastic differentiation of vascular smooth muscle cells through the PI3K/AKT and Wnt/β-catenin pathway

2021 ◽  
Author(s):  
Yun Zhou ◽  
Li-Long Wei ◽  
Rui-Ping Zhang ◽  
Cheng-Wu Han ◽  
Yongtong Cao
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Osteoblastic Differentiation ◽  
Alizarin Red S ◽  
Regulation Mechanism ◽  
Alizarin Red ◽  
Globular Adiponectin

AbstractLipid metabolism is closely related to the improvement of vascular calcification (VC) in chronic kidney disease (CKD). Globular adiponectin (gAd) has been reported to be involved in the development of VC in CKD, but the detailed regulatory role remains unclear. The present study is aimed to investigate the biological function and the underlying regulation mechanism of gAd in the process of VC during CKD. Vascular smooth muscle cells (VSMCs) calcification was determined by Alizarin Red S staining. Protein signaling related with VC was tested by western blotting. The expression and intracellular localization of runt-related transcription factor 2 (Runx2) was detected by immunofluorescence and uraemic rat with VC was established by a two-step nephrectomy. Combined with the results of Alizarin Red S staining, we discovered that β-glycerophosphate (β-Gp)-induced the osteoblastic differentiation of VSMCs was significantly reversed by gAd treatment. Along with the VSMCs calcification and the increase of Runx2 in β-Gp-exposed VSMCs, the activities of protein kinase B (AKT) and Wnt/β-catenin pathway were enhanced, but that were counteracted by the exposure of gAd in rat and human VSMCs. After administration with agonists of the Wnt (SKL2001) and AKT (SC79), there appeared more osteoblastic differentiation and higher expression of Runx2 in gAd-treated VSMCs, but showing lower impact in the presence of SC79 than that in the presence of SKL2001. In the in vivo experiments, intravenous injection of gAd also significantly inhibited VC and Runx2 level in uraemic rat in a dose-dependent manner, possibly through regulating Wnt/β-catenin pathway. This study demonstrates that gAd ameliorates osteoblastic differentiation of VSMCs possibly by blocking PI3K/AKT and Wnt/β-catenin signaling transduction. The findings provide an important foundation for gAd in treating VC in kidney diseases.

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