Long‐term application of the aldosterone antagonist spironolactone prevents stiff endothelial cell syndrome

Drüppel, Verena; Kusche-Vihrog, Kristina; Großmann, Claudia; Gekle, Michael; Kasprzak, Bernd; Brand, Eva; Pavenstädt, Hermann; Oberleithner, Hans; Kliche, Katrin

doi:10.1096/fj.13-228312

Cited by 74 publications

(66 citation statements)

References 39 publications

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“…It was shown that the MR is increased in whole vessel preparations of old rats 21 and in an in vitro model of aging endothelia. 16 In the latter, EnNaC mRNA was found elevated, too. Considering that aldosterone was present in all experimental groups, the increase in EnNaC might, therefore, be the result of increased agonist/receptor interaction followed by gene transcription.…”

Section: Discussionmentioning

confidence: 96%

“…16 Aortic preparations were fixed in glutaraldehyde (final concentration, 0.1%) for 30 minutes. Because the α-EnNaC subunit is crucial for EnNaC function, a primary polyclonal rabbit anti-α-epithelial sodium channel antibody (Santa Cruz, Heidelberg, Germany; dilution 1:250) was applied.…”

Section: Quantification Of Ennac Molecules In the Ec Surfacementioning

confidence: 99%

“…Stiffness of the EC cortex was assessed by atomic force microscopy on living ex vivo aortae as described by Kusche-Vihrog et al 15 and Drüppel et al 16 During atomic force microscopy experiments, aortic preparations were continuously perfused with HEPES-buffered solution (in mmol/L: 5 KCl, 1 MgCl 2 , 1 CaCl 2 , 5 glucose and 10 HEPES) containing the agent(s) of the respective treated group. At the beginning of each experiment, HEPES buffer containing 135 mmol/L sodium (normal) was used, and cortical stiffness of 20 individual ECs was assessed.…”

Section: Measurements Of Ec Stiffnessmentioning

confidence: 99%

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Endothelial Sodium Channels Trigger Endothelial Salt Sensitivity With Aging

et al. 2014

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Section: Discussionmentioning

confidence: 96%

Section: Quantification Of Ennac Molecules In the Ec Surfacementioning

confidence: 99%

Section: Measurements Of Ec Stiffnessmentioning

confidence: 99%

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Endothelial Sodium Channels Trigger Endothelial Salt Sensitivity With Aging

et al. 2014

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“…The aldosterone antagonist spironolactone, which is used as antihypertensive drug and suppresses cardiac fibrosis, suppresses such endothelial stiffening. 126,127 This is because spironolactone blocks aldosterone-induced transport of ENaC to the plasma membrane. Furthermore, the ENaC blocker amiloride reduces hypertension and patients with Liddle syndrome benefit from treatment with amiloride.…”

Section: Shear Stress-regulated Ion Channelsmentioning

confidence: 99%

Between Rho(k) and a Hard Place

Huveneers

Daemen

Hordijk

2015

Circulation Research

157

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Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. vascular stiffening) and the various external cues that regulate this. In addition, we will discuss the relationship between endothelial contractility and leukocyte extravasation and finally address (future) possibilities to therapeutically target ECs to reduce chronic, stiffness-related, vascular inflammation. Systemic Regulation of Vascular StiffnessArterial stiffness is strongly associated with high blood pressure, as well as with aging, and serves as an independent predictor of human cardiovascular disease. An elevation in arterial stiffness increases systolic blood pressure, thereby promoting cardiac hypertrophy, and decreases the diastolic blood pressure which is a trigger for developing myocardial ischemia. 7 Aortic stiffness also affects the microcirculation and vice versa, microcirculatory changes affect aortic stiffness. Stiffening of the aortic wall leads to increased pulse wave velocity (PWV) and premature reflected waves with elevated systolic and pulsatile central hemodynamic load resulting in microcirculatory damages in peripheral tissues. Conversely, microvasculature remodeling elevates systemic vascular resistance and pulse wave reflection, which stiffens the aortic wall, indicating that the endothelium has both a responsive and a causal role in vascular stiffening. 7 Increased PWV accurately estimates arterial wall stiffness and has recently been included in official hypertension guidelines. PWV values increase with age, and increases in aortic PWV is a g...

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“…101 Decrease of Na + entry lowers the work load of the respective epithelial cell and thus protects against energy depletion. As enhanced expression of endothelial ENaC is followed by endothelial stiffening with decreased endothelial NO release, 101,102 reduction of ENaC activity by AMPK may at least in theory contribute to the stimulation of AMPK-sensitive endothelial NO release following ischemia. 103 AMPK contributes to the regulation of the pore-forming subunits of Ca 2+ release activated Ca 2+ channels Orai1, Orai2, and Orai3 ( Fig.…”

mentioning

confidence: 99%