Wednesday, April 2, 2025
4/2/2025
Epithelial sodium channels in endothelial cells and arterial stiffening - Project Summary/Abstract Epidemiological data have established an increased incidence of cardiovascular disease events in obese individuals, with these events being strongly associated with excessive arterial stiffness. Elevated aldosterone levels and activation of vascular mineralocorticoid receptors (MRs) contribute to obesity related arterial stiffening. Studies by our group and others have further shown that enhanced endothelial cell (EC) mineralocorticoid receptor (ECMR) and its downstream epithelial sodium channel (EnNaC) signaling, induce arterial and EC stiffening together with oxidative stress and inflammation. Conversely, ECMR/EnNaC deletion prevents diet or aldosterone induced excessive endothelial and arterial stiffness. Our recent data further indicate that activation of the ECMR increases expression of EC deubiquitinating enzymes and that endothelial ubiquitin-specific protease 8 (ECUSP8) plays a dominant role in preventing EnNaC ubiquitination and degradation, leading to increases in EC endosomal EnNaC. Moreover, enhanced ECMR/ECUSP8 signaling also promotes endosomal EnNaC trafficking and release of exosomal EnNaC. Importantly, exosomal EnNaC, released from endosomes, is re-uptaken and in turn impacts on EC/vascular smooth muscle cell (VSMC) and arterial stiffening. Our research hypothesis is that ECMR activation enhances ECUSP8 signaling that increases endosomal EnNaC, endosome trafficking, plasma membrane EnNaC, and release of exosomal EnNaC, resulting in EC/VSMC and arterial stiffening. This notion is supported by the fact that obesity is a major public health issue in the United States, and it is associated with cardiovascular MR activation and vascular disease. To address this hypothesis in vivo and in vitro, models of ECMR/ECUSP8/EnNaC activation will include a high fat, high sucrose diet (diet induced obesity) and aldosterone administration, respectively. A cross-sectional human study will be included to investigate the correlation between plasma exosomal EnNaC and arterial stiffening in clinically obese and hypertensive patients. Aim 1 of this application proposes to determine whether ECMR activation enhances ECUSP8 signaling that increases endosomal EnNaC, endosome trafficking, plasma membrane EnNaC content, and EC and arterial stiffening. Aim 2 will determine determine whether ECUSP8 signaling increases release of EC derived exosomal EnNaC that is uptaken by ECs/VSMCs and in turn impacts on arterial stiffening. The proposed innovative research program will provide enhanced understanding of the interactions between ECMR/ECUSP8/EnNaC activation, endosome trafficking, release of exosmes, and identify novel therapeutic targets and strategies for the early diagnosis and prevention of obesity induced vascular stiffening and related cardiovascular complications.
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