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Endothelial AGGF1 Deficiency Causes Mitochondrial Dysfunction and Contributes to Age-Elevated Blood Pressure
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DOI：10.1111/acel.70652.png)
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Abstract
En 中文
Endothelial cells are critical in the regulation of blood pressure. We previously demonstrated AGGF1 was crucial for maintaining endothelial cell function. This study aims to examine whether AGGF1 regulates blood pressure. Here, we found that AGGF1 expression was inversely correlated with blood pressure with age. In male mice, endothelial-specific loss of function of Aggf1 (Aggf1flox/flox/Tie2-Cre+) significantly increased blood pressure, whereas endothelial-specific human AGGF1 overexpression (TGM(Tie2-hAGGF1)) suppressed age-elevated blood pressure. The endothelial-specific loss of AGGF1 accelerated early vascular aging, characterized by increased arterial stiffness, impaired endothelium-dependent vasorelaxation, reduced eNOS phosphorylation, and augmented ROS production, whereas AGGF1 overexpression rescued these phenotypic changes. Mechanistically, we found that nuclear-localized AGGF1 bound to the SESN2 promoter and enhanced its transcription. This upregulation of SESN2 attenuated mitochondrial dysfunction, including respiratory dysfunction and elevated mitochondrial ROS, and ultimately led to increased p-eNOS levels and improved endothelial function. Furthermore, SESN2 overexpression rescued early vascular aging and reduced blood pressure in Aggf1flox/flox/Tie2-Cre+ mice, while SESN2 knockdown attenuated the beneficial vascular effects of AGGF1. Together, we demonstrate that endothelial AGGF1/SESN2/p-eNOS is a novel and important signaling axis in the maintenance of blood pressure. Age suppresses the AGGF1/SESN2/p-eNOS signaling cascade, leading to an elevation of blood pressure. Our study provides new insights into age-elevated blood pressure in male mice and suggests AGGF1 as a potentially valuable target for prehypertension intervention in the elderly male population.
Keywords:
AGGF1
blood pressure
early vascular aging
endothelial cell
mitochondrial dysfunction
SESN2
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