C-Reactive Protein Makes Human Endothelium Stiff and Tight

Abstract

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. (Hypertension. 2011; 57:231-237.)Key Words: aldosterone Ⅲ CRP Ⅲ ENaC Ⅲ AFM Ⅲ immunofluorescence Ⅲ PI3K Ⅲ NO C -Reactive protein (CRP) is considered to be a stable and powerful inflammatory marker of future cardiovascular risk 1 and, as an acute-phase reactant, originally considered to be a mere marker of vascular inflammation. However, CRP may also participate directly in the inflammatory process. 2 During inflammation and sepsis, the production of NO is increased, which leads to vasodilation and thus to a drop in blood pressure. 3,4 Recently, CRP was shown to decrease endothelial NO synthase expression 5 via inhibition of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, 6 which suggests that it also has a role in endothelial (dys)function. In clinical studies, it has been shown that in patients with essential hypertension, there is a positive correlation between CRP levels and pulse wave velocity, which is a functional indicator for arterial stiffness. 7,8 When the paradigm shift occurred that CRP was not merely a "reporting" but also an "acting" protein, another shift in understanding took place, namely that the mineralocorticoid hormone aldosterone not only acts on the kidney but also on the cardiovascular sys...

Soluble Adenylyl Cyclase in Vascular Endothelium

“…Mice aortae (n=4) for atomic force microscopy (AFM)-based cell stiffness measurements were dissected, freed from surrounding tissue, opened and fixed on glass coverslips coated with Cell-Tak (Becton Dickinson, Heidelberg, Germany) as described previously. 28 Aortae were incubated for 24 hours in medium with KH7 (25 μmol/L) and aldosterone (1 nmol/L) or aldosterone alone.…”

Stiff Endothelial Cell Syndrome in Vascular Inflammation and Mineralocorticoid Excess

“…7 Using immunofluorescence, Kusche-Vihrog et al now present evidence that C-reactive protein (25 mg/L) fosters the insertion of ENaC into the cell membrane of cultured endothelial cells. 8 Using atomic force microscopy, they demonstrate that C-reactive protein (Ն25 mg/L) enhances the stiffness of those cells. 8 The effect on the stiffness was abrogated by the ENaC inhibitor amiloride (1 mol/L) or by a 24-hour pretreatment with the mineralocorticoid receptor blocker spironolactone (5 nmol/L).…”

Pulsatile Stress, Inflammation and Change in Arterial Stiffness

“…In chronic hemodialysis patients, C-reactive protein is a better predictor of mortality than even PWV 19) . It has been suggested that inflammation contributes to endothelial dysfunction and consequently decreases small and large artery elasticity 20) . Indeed, several studies have noted associations between endothelial function and PWV 21) .…”