Pulsatile Atheroprone Shear Stress Affects the Expression of Transient Receptor Potential Channels in Human Endothelial Cells

Department of Nephrology, Charité Campus Benjamin Franklin, Berlin, Germany.
Hypertension (Impact Factor: 7.63). 05/2012; 59(6):1232-40. DOI: 10.1161/HYPERTENSIONAHA.111.183608
Source: PubMed

ABSTRACT The goal of the study was to assess whether pulsatile atheroprone shear stress modulates the expression of transient receptor potential (TRP) channels, TRPC3, TRPC6, TRPM7, and TRPV1 mRNA, in human umbilical vascular endothelial cells. Exposure of cultured vascular endothelial cells to defined shear stress, producing a constant laminar flow (generating a shear stress of 6 dyne/cm(2)), laminar pulsatile atheroprotective flow (with a mean shear stress of 20 dyne/cm(2)), or laminar atheroprone bidirectional flow (with a mean shear stress of 0 dyne/cm(2)) differentially induced TRPC6 and TRPV1 mRNA as measured by quantitative real-time RT-PCR and normalized to GAPDH expression. Thereby, TRPC6 and TRPV1 mRNA expressions were significantly increased after 24 hours of exposure to an atheroprone flow profile compared with an atheroprotective flow profile. Furthermore, the expression of transcription factors GATA1 and GATA4 was significantly correlated with the expression of TRPC6 mRNA. In contrast, after 24 hours of constant laminar flow, the expression of TRPC6 and TRPV1 mRNA was unchanged, whereas the expression of TRPC3 and TRPM7 was significantly higher in endothelial cells exposed to shear stress in comparison with endothelial cells grown under static conditions. There was a significant association between the expression of TRPC6 and tumor necrosis factor-α mRNA in human vascular tissue. No-flow and atheroprone flow conditions are equally characterized by an increase in the expression of tumor necrosis factor-α; however, inflammation-associated endothelial cell reactions may be further aggravated at atheroprone flow conditions by the increase of TRPV1 and TRPC6, as observed in our study.

  • [Show abstract] [Hide abstract]
    ABSTRACT: TRPC6 is a non-selective cation channel 6 times more permeable to Ca(2+) than to Na(+). Channel homotetramers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are directly activated by the second messenger diacylglycerol (DAG). TRPC6 proteins are also regulated by specific tyrosine or serine phosphorylation and phosphoinositides. Given its specific expression pattern, TRPC6 is likely to play a number of physiological roles which are confirmed by the analysis of a Trpc6 (-/-) mouse model. In smooth muscle Na(+) influx through TRPC6 channels and activation of voltage-gated Ca(2+) channels by membrane depolarisation is the driving force for contraction. Permeability of pulmonary endothelial cells depends on TRPC6 and induces ischaemia-reperfusion oedema formation in the lungs. TRPC6 was also identified as an essential component of the slit diaphragm architecture of kidney podocytes and plays an important role in the protection of neurons after cerebral ischaemia. Other functions especially in immune and blood cells remain elusive. Recently identified TRPC6 blockers may be helpful for therapeutic approaches in diseases with highly activated TRPC6 channel activity.
    Handbook of experimental pharmacology 01/2014; 222:157-88. DOI:10.1007/978-3-642-54215-2_7
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial cells (ECs) are constantly exposed to chemical and mechanical microenvironment in vivo. In mechanotransduction, cells can sense and translate the extracellular mechanical cues into intracellular biochemical signals, to regulate cellular processes. This regulation is crucial for many physiological functions, such as cell adhesion, migration, proliferation, and survival, as well as the progression of disease such as atherosclerosis. Here, we overview the current molecular understanding of mechanotransduction in ECs associated with atherosclerosis, especially those in response to physiological shear stress. The enabling technology of live-cell imaging has allowed the study of spatiotemporal molecular events and unprecedented understanding of intracellular signaling responses in mechanotransduction. Hence, we also introduce recent studies on mechanotransduction using single-cell imaging technologies.
    Progress in molecular biology and translational science 01/2014; 126:25-51. DOI:10.1016/B978-0-12-394624-9.00002-6 · 3.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent preclinical data indicate that activators of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) may improve the outcome of ischaemic acute kidney injury (AKI). The underlying mechanisms are unclear, but may involve TRPV1 channels in dorsal root ganglion neurones that innervate the kidney. Recent data identified TRPV4, together with TRPV1, to serve as major calcium influx channels in endothelial cells. In these cells, gating of individual TRPV4 channels within a four-channel cluster provides elementary calcium influx (calcium sparklets) to open calcium-activated potassium channels and promote vasodilation. The TRPV receptors can also form heteromers that exhibit unique conductance and gating properties, further increasing their spatio-functional diversity. This review summarizes data on electrophysiological properties of TRPV1/4 and their modulation by endogenous channel agonists such as 20-HETE, phospholipase C and phosphatidylinositide 3-kinase (PI3 kinase). We review important roles of TRPV1 and TRPV4 in kidney physiology and renal ischaemia reperfusion injury; further studies are warranted to address renoprotective mechanism of vanilloid receptors in ischaemic AKI including the role of the capsaicin receptor TRPV1 in primary sensory nerves and/or endothelium. Particular attention should be paid to understand the kidneys' ability to respond to ischaemic stimuli after catheter-based renal denervation therapy in man, whereas the discovery of novel pharmacological TRPV modulators may be a successful strategy for better treatment of acute or chronic kidney failure.
    Acta Physiologica 03/2013; 207(3). DOI:10.1111/apha.12051 · 4.25 Impact Factor