Key result
Interference with endothelial PPAR-γ in mice fed a low-salt diet for 6 weeks produced accelerated cerebral vascular dysfunction mediated by AT1 receptor activation and perturbed redox homeostasis.
Interference with endothelial PPAR-γ produces cerebral vascular dysfunction in response to low salt-mediated activation of the endogenous renin-angiotensin system, highlighting the sensitivity of the cerebral circulation to perturbed redox homeostasis.
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Endothelial PPAR-γ may protect cerebral vessels during low-salt/RAS activation; leaves open clinical relevance in patients with endothelial dysfunction.
Low-salt diet is beneficial in salt-sensitive hypertension but may provoke cardiovascular risk in patients with heart failure, diabetes mellitus, or other cardiovascular abnormalities because of endogenous renin-angiotensin system activation. PPAR (peroxisome proliferator-activated receptor)-γ is a transcription factor which promotes an antioxidant pathway in the endothelium. We studied transgenic mice expressing a dominant-negative mutation in PPAR-γ selectively in the endothelium (E-V290M) to test the hypothesis that endothelial PPAR-γ plays a protective role in response to low salt-mediated renin-angiotensin system activation. Plasma renin and Ang II (angiotensin II) were significantly and equally increased in all mice fed low salt for 6 weeks. Vasorelaxation to acetylcholine was not affected in basilar artery from E-V290M at baseline but was significantly and selectively impaired in E-V290M after low salt. Unlike basilar artery, low salt was not sufficient to induce vascular dysfunction in carotid artery or aorta. Endothelial dysfunction in the basilar artery from E-V290M mice fed low salt was attenuated by scavengers of superoxide, inhibitors of NADPH oxidase, or blockade of the Ang II AT1 (angiotensin type-1) receptor. Simultaneous AT1 and AT2 receptor blockade revealed that the restoration of endothelial function after AT1 receptor blockade was not a consequence of AT2 receptor activation. We conclude that interference with PPAR-γ in the endothelium produces endothelial dysfunction in the cerebral circulation in response to low salt-mediated activation of the endogenous renin-angiotensin system, mediated at least in part, through AT1 receptor activation and perturbed redox homeostasis. Moreover, our data suggest that the cerebral circulation may be particularly sensitive to inhibition of PPAR-γ activity and renin-angiotensin system activation.
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Nair et al. (2018) studied Endothelial dysfunction. Low-salt diet vs. Baseline was evaluated on Vasorelaxation to acetylcholine in basilar artery. Interference with endothelial PPAR-γ in mice fed a low-salt diet for 6 weeks produced accelerated cerebral vascular dysfunction mediated by AT1 receptor activation and perturbed redox homeostasis.
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