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Caveolae and rho kinase

Adrienn Krauszman, Tak W Mak, Katalin Szaszi, Wolfgang M Kuebler
Aims: Hypoxic pulmonary vasoconstriction (HPV) redistributes blood flow from poorly ventilated to better aerated areas in the lung, thereby optimizing ventilation-perfusion ratio (V/Q). Pulmonary artery smooth muscle cell (PASMC) contraction in response to hypoxia is triggered by Ca2+ influx via transient receptor potential canonical 6 (TRPC6) cation channels that have translocated to caveolae in the plasma membrane. Since phosphatase and tensin homolog (PTEN) was suggested to regulate TRPC6 in endothelial cells, we aimed to define its role in the hypoxic response of PASMCs and as a putative mediator of HPV...
July 1, 2017: Cardiovascular Research
Yongfu Lu, Lihong Tang, Yiqiao Li, Qiang He
Increasing evidence indicates that diabetes-mediated renal interstitial fibrosis through extracellular matrix (ECM) protein accumulation is an important event in the development of diabetic kidney disease (DKD), however, the underlying mechanism remains unclear. In the current study, it was observed that high levels of glucose (HG) time‑ and dose-dependently increased the production of the ECM protein, fibronectin (FN), in primary rat mesangial cells. Inhibition of the Rho pathway blocked HG‑induced FN upregulation...
July 2016: Molecular Medicine Reports
Karl Swärd, Karin G Stenkula, Catarina Rippe, Azra Alajbegovic, Maria F Gomez, Sebastian Albinsson
Members of the myocardin family bind to the transcription factor serum response factor (SRF) and act as coactivators controlling genes of relevance for myogenic differentiation and motile function. Binding of SRF to DNA is mediated by genetic elements called CArG boxes, found often but not exclusively in muscle and growth controlling genes. Studies aimed at defining the full spectrum of these CArG elements in the genome (i.e. the CArGome) have in recent years, unveiled unexpected roles of the myocardin family proteins in lipid and glucose homeostasis...
September 1, 2016: Journal of Physiology
Christoph Tabeling, Hanpo Yu, Liming Wang, Hannes Ranke, Neil M Goldenberg, Diana Zabini, Elena Noe, Adrienn Krauszman, Birgitt Gutbier, Jun Yin, Michael Schaefer, Christoph Arenz, Andreas C Hocke, Norbert Suttorp, Richard L Proia, Martin Witzenrath, Wolfgang M Kuebler
Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo...
March 31, 2015: Proceedings of the National Academy of Sciences of the United States of America
Zhen Li, Yun-hui Liu, Yi-xue Xue, Li-bo Liu, Ping Wang
Low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) can selectively increase blood-tumor barrier (BTB) permeability via the paracellular pathway. The role of the transcellular pathway in this process is unclear. This study was conducted to evaluate the potential involvement of the transcellular pathway in EMAP-II-induced opening of the BTB and to identify the associated mechanisms. Evans blue extravasation test was used to measure changes in BTB permeability after EMAP-II (80 ng/kg) administration in a rat model of C6 glioma...
March 2014: Journal of Molecular Neuroscience: MN
B Sommer, L M Montano, J Chávez, V Carbajal, L M García-Hernandez, C Irles, A M Jiménez-Garduno, A Ortega
Airway smooth muscle (ASM) membrane depolarization through KCl opens L-type voltage dependent Ca2+ channels (Ca(v)1.2); its opening was considered the cause of KCl contraction. This substance is used to bypass intracellular second messenger pathways. It is now clear that KCl also activates RhoA/Rho kinase (ROCK) pathway. ROCK isoforms are characterized as ROCK1 and ROCK2. Because ROCK1 seems the most abundant isotype in lung, we studied its participation in KCl stimulated bovine ASM. With methyl-beta-cyclodextrin (MbetaCD) we disrupted caveolae, a membrane compartment considered as the RhoA/ROCK assembly site, and found that KCl contraction was reduced to the same extent (~26%) as Y-27632 (ROCK inhibitor) treated tissues...
2014: Physiological Research
Sunila Mahavadi, Sayak Bhattacharya, Divya P Kumar, Chereena Clay, Gracious Ross, Hamid I Akbarali, John R Grider, Karnam S Murthy
Caveolae are specialized regions of the plasma membrane that concentrate receptors and associated signaling molecules critical in regulation of cellular response to transmitters and hormones. We have determined the effects of caveolin-1 (Cav-1) deletion, caveolin-1 siRNA, and caveolar disruption in mice on the signaling pathways that mediate contraction and relaxation in colonic smooth muscle and on the components of the peristaltic reflex in isolated tissue and propulsion in intact colonic segments. In Cav-1-/- mice, both relaxation and contraction were decreased in smooth muscle cells and muscle strips, as well as during both phases of the peristaltic reflex and colonic propulsion...
December 2013: American Journal of Physiology. Gastrointestinal and Liver Physiology
Sayak Bhattacharya, Sunila Mahavadi, Othman Al-Shboul, Senthilkumar Rajagopal, John R Grider, Karnam S Murthy
Caveolae act as scaffolding proteins for several G protein-coupled receptor signaling molecules to regulate their activity. Caveolin-1, the predominant isoform in smooth muscle, drives the formation of caveolae. The precise role of caveolin-1 and caveolae as scaffolds for G protein-coupled receptor signaling and contraction in gastrointestinal muscle is unclear. Thus the aim of this study was to examine the role of caveolin-1 in the regulation of Gq- and Gi-coupled receptor signaling. RT-PCR, Western blot, and radioligand-binding studies demonstrated the selective expression of M2 and M3 receptors in gastric smooth muscle cells...
August 1, 2013: American Journal of Physiology. Cell Physiology
Tingting Wu, Baifang Zhang, Feng Ye, Zeling Xiao
VEGF is known to be an endothelial cell mitogen that stimulates angiogenesis by promoting endothelial cell survival, proliferation, migration, and differentiation. Recent studies have suggested that VEGF may play a pivotal role in glomerular sclerosis through extracellular matrix protein (ECM) accumulation, although the signaling mechanism is still unclear. The GTPase RhoA has been implicated in VEGF-induced type IV collagen accumulation in some settings. Here we study the role of different VEGF receptors and membrane microdomain caveolae in VEGF-induced RhoA activation and fibronectin upregulation in mesangial cells (MCs)...
March 15, 2013: American Journal of Physiology. Renal Physiology
Bharat Joshi, Michele Bastiani, Scott S Strugnell, Cecile Boscher, Robert G Parton, Ivan R Nabi
Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes...
October 29, 2012: Journal of Cell Biology
Daniel W Nuno, Sarah K England, Kathryn G Lamping
Vascular smooth muscle contraction occurs following an initial response to an increase in intracellular calcium concentration and a sustained response following increases in the sensitivity of contractile proteins to calcium (calcium sensitization). This latter process is regulated by the rhoA/rho kinase pathway and activated by serotonin. In multiple cell types, signaling molecules compartmentalize within caveolae to regulate their activation. We hypothesized that serotonin differentially compartmentalizes rhoA within caveolar versus noncaveolar lipid rafts to regulate sustained vascular contractions...
November 1, 2012: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Jae Hong Park, Jung Min Ryu, Seung Pil Yun, Mi Ok Kim, Ho Jae Han
BACKGROUND: Extracellular matrix (ECM) components and intracellular pH (pH(i)) may serve as regulators of cell migration in various cell types. METHODS: The Oris migration assay was used to assess the effect of fibronectin (FN) on cell motility. The Na(+)/H(+) exchanger (NHE)-1 activity was evaluated by measuring pH(i) and [(22)Na(+)] uptake. To examine activated signaling molecules, western blot analysis and immunoprecipitation was performed. RESULTS: ECM components (FN, laminin, fibrinogen, and collagen type I) increased [(22)Na(+)] uptake, pH(i), and cell migration...
October 2012: Biochimica et Biophysica Acta
Dylan Burger, Augusto C Montezano, Nobuhiro Nishigaki, Ying He, Anthony Carter, Rhian M Touyz
OBJECTIVE: Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs). METHODS AND RESULTS: Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy...
August 2011: Arteriosclerosis, Thrombosis, and Vascular Biology
Katia Fecchi, Sara Travaglione, Francesca Spadaro, Adriano Quattrini, Isabella Parolini, Giovanni Piccaro, Carla Raggi, Alessia Fabbri, Federica Felicetti, Alessandra Carè, Carla Fiorentini, Massimo Sargiacomo
Caveolae have been indicated as a center of cytoskeleton regulation for Src kinase/Rho GTPase signaling. In addition, Src recruitment on intact cortical actin cytoskeleton appears to be required for bFGF/FGFR signal activation. Recently, we established a relationship between caveolin-1 (Cav-1) expression and cell migration in human malignant melanoma, constitutively activated by a bFGF autoregulatory loop. This work intends to investigate whether caveolae's asset, through bFGF/FGFR/c-Src/Rho signaling, could be related to melanoma cell anchorage...
March 15, 2012: International Journal of Cancer. Journal International du Cancer
Gemma C Carter, Laura Bernstone, Darshan Baskaran, William James
Recent studies provide compelling evidence that HIV-1 entry in cell lines and lymphocytes proceeds by endocytosis, but these studies are still lacking in macrophages, an important natural target cell for HIV-1. Macrophages exhibit continual and extensive endocytic activity as part of their natural functions, so we investigated the uptake pathways involved in productive HIV-1 entry. We find that caveolae are not utilised by HIV-1, because the main structural proteins, caveolin-1 and 2 are absent from most human leukocytes...
January 20, 2011: Virology
Ahmed Chahdi, Andrey Sorokin
Endothelin-1 (ET-1) is a potent mitogen that transmits signals through its cognate G protein-coupled receptors to stimulate extracellular signal-regulated kinase Erk1/2. Endothelin-1 receptors (ET-Rs) are known to interact with caveolin-1 and co-localize in caveolae which integrate different receptor and signaling proteins. We have recently shown that beta(1)Pix binds specifically to ET-Rs. Here, we show that beta(1)Pix binding to caveolin-1 is dependent on heterotrimeric G proteins activation state. beta(1)Pix interaction with different G proteins is increased in the presence of the G protein activator AMF...
January 15, 2010: Biochemical and Biophysical Research Communications
Seong-Youl Kim, Teng-ke Wang, Raman Deep Singh, Christine L Wheatley, David L Marks, Richard E Pagano
Plasma membrane (PM) microdomains, including caveolae and other cholesterol-enriched subcompartments, are involved in the regulation of many cellular processes, including endocytosis, attachment and signaling. We recently reported that brief incubation of human skin fibroblasts with the synthetic glycosphingolipid, D-erythro-octanoyl-lactosylceramide (C8-D-e-LacCer), stimulates endocytosis via caveolae and induces the appearance of micron-size microdomains on the PM. To further understand the effects of C8-D-e-LacCer treatment on PM microdomains, we used a detergent-free method to isolate microdomain-enriched membranes from fibroblasts treated +/-C8-D-e-LacCer, and performed 2-DE and mass spectrophotometry to identify proteins that were altered in their distribution in microdomains...
September 2009: Proteomics
Shintaro Fumoto, Junya Nishi, Hiroki Ishii, Xuan Wang, Hirotaka Miyamoto, Naoki Yoshikawa, Mikiro Nakashima, Junzo Nakamura, Koyo Nishida
We have recently discovered the potential for in vivo naked plasmid DNA (pDNA) transfer into gastric serosal surface cells in mice. As pDNA are huge molecules, the mechanism of gene transfer without carriers and physical forces is of great biological interest. The endocytic route for naked pDNA transfer into gastric mesothelial cells was not clathrin- or caveolae-mediated endocytosis, but macropinocytosis. Naked pDNA transfer required both actin polymerization and myosin-based contraction. Upstream kinases of Rho family GTPases, Syk, Src family kinases and PI-3K were involved in naked pDNA transfer...
July 2009: Molecular Pharmaceutics
Sita Somara, Robert R Gilmont, Robert G Dennis, Khalil N Bitar
BACKGROUND & AIMS: The internal anal sphincter (IAS) is a specialized circular smooth muscle that maintains rectoanal continence. In vitro models are needed to study the pathophysiology of human IAS disorders. We bioengineered sphincteric rings from human IAS smooth muscle cells (SMC) and investigated their response to cholinergic stimulation as well as investigated whether protein kinase C (PKC) and Rho kinase signaling pathways remain functional. METHODS: 3-Dimensional bioengineered ring (3DBR) model of the human IAS was constructed from isolated human IAS SMC obtained from surgery...
July 2009: Gastroenterology
Bettina Sommer, Luis M Montaño, Verónica Carbajal, Edgar Flores-Soto, Alicia Ortega, Ricardo Ramírez-Oseguera, Claudine Irles, Ahmed F El-Yazbi, Woo Jung Cho, Edwin E Daniel
Some receptors and signaling molecules, such as Rho-kinase (ROCK), localize in caveolae. We asked whether the function of histamine receptors (H(1)) and 5-hydroxytryptamine (serotonin) receptors (5-HT(2A)) in bovine tracheal smooth muscle are modified after caveolae disruption and if so, whether the altered ROCK activity plays a role in this modification. Methyl-beta-cyclodextrin (MbetaCD), used to deplete membrane cholesterol, was shown to disrupt caveolae and diminish sustained contractions to histamine (approximately 80%), 5-HT (100%), alpha-methyl-5-HT (100%), and KCl (approximately 30%)...
March 2009: Canadian Journal of Physiology and Pharmacology
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