title: C-reactive protein makes human endothelium stiff and tight.
abstract: Elevation of C-reactive protein (CRP) in human blood accompanies inflammatory processes, including cardiovascular diseases. There is increasing evidence that the acute-phase reactant CRP is not only a passive marker protein for systemic inflammation but also affects the vascular system. Further, CRP is an independent risk factor for atherosclerosis and the development of hypertension. Another crucial player in atherosclerotic processes is the mineralocorticoid hormone aldosterone. Even in low physiological concentrations, it stimulates the expression and membrane insertion of the epithelial sodium channel, thereby increasing the mechanical stiffness of endothelial cells. This contributes to the progression of endothelial dysfunction. In the present study, the hypothesis was tested that the acute application of CRP (25 mg/L), in presence of aldosterone (0.5 nmol/L; 24 hour incubation), modifies the mechanical stiffness and permeability of the endothelium. We found that endothelial cells stiffen in response to CRP. In parallel, endothelial epithelial sodium channel is inserted into the plasma membrane, while, surprisingly, the endothelial permeability decreases. CRP actions are prevented either by the inhibition of the intracellular aldosterone receptors using spironolactone (5 nmol/L) or by the inactivation of epithelial sodium channel using specific blockers. In contrast, inhibition of the release of the vasodilating gas nitric oxide via blockade of the phosphoinositide 3-kinase/Akt pathway has no effect on the CRP-induced stiffening of endothelial cells. The data indicate that CRP enhances the effects of aldosterone on the mechanical properties of the endothelium. Thus, CRP could counteract any decrease in arterial blood pressure that accompanies severe acute inflammatory processes.
authors.affiliation: Institute of Physiology II, Muenster, Germany. kusche@uni-muenster.de
authors.forename: Kristina
authors.initials: K
authors.lastname: Kusche-Vihrog
authors.forename: Katarina
authors.initials: K
authors.lastname: Urbanova
authors.forename: Anja
authors.initials: A
authors.lastname: Blanqué
authors.forename: Marianne
authors.initials: M
authors.lastname: Wilhelmi
authors.forename: Hermann
authors.initials: H
authors.lastname: Schillers
authors.forename: Katrin
authors.initials: K
authors.lastname: Kliche
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.forename: Hans
authors.initials: H
authors.lastname: Oberleithner
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000494:pharmacology*; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D018625:Microscopy, Atomic Force; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019810:Sodium Azide / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014665:Vasodilator Agents; C013407:benzamil; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000450:Aldosterone; D000584:Amiloride; D002097:C-Reactive Protein; D019810:Sodium Azide