Abstract: TH-OR78
Endoplasmic Reticulum Stress Immediate Early Response 3 Gene Mediates Myeloid-Specific Salt-Sensitive Hypertension in Humans
Session Information
- Hypertension and CVD: Research Advances
October 24, 2024 | Location: Room 5, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Afolabi, Jeremiah M., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Kirabo, Annet, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Salt sensitivity of blood pressure is a significant risk factor for cardiovascular morbidity and mortality, and currently lacks a diagnostic marker or established treatment protocol. Our previous research indicated that immune cells play a role in salt-sensitive hypertension, but the specific mechanisms are not fully understood. Expression of the early response gene, Immediate early response 3 (IER3) is induced by varying forms of cellular stress and proinflammatory cytokines, but its role in salt-sensitive hypertension is unknown. We hypothesize that high dietary salt intake activates IER3 expression via proinflammatory signaling thereby contributing to salt-sensitive hypertension.
Methods
To test this hypothesis, we conducted bulk RNA sequencing analysis on isolated human monocytes with and without high salt. We also performed in vivo studies on humans living with hypertension using the rigorous Weinberger protocol, followed by single-cell transcriptome profiling using RNA-Seq analysis in peripheral blood mononuclear cells (PBMCs).
Results
We found that in vitro high salt treatment increased human monocyte expression of the ER stress marker, ATF4 (5216.09 ± 343.86 vs 7566 ± 549.17, p=0.0014), in addition to TNF-α (117.09 ± 23.71 vs 357.82 ± 59.62, p=0.0013), FAS (201.45 ± 25.42 vs 422.64 ± 52.15, p=0.0024), NFKB2 (4182.18 ± 401.24 vs 6061.82 ± 692.49, p=0.0192), and IER3 (10146.64 ± 2868.74 vs 19009.09 ± 5343.53, p=0.0759) when compared to normal salt (n=11). In vivo single cell transcriptomic analysis in PBMCs revealed that in response to high salt treatment, IER3 expression changes dynamically with blood pressure (Diastolic Blood Pressure (DBP): r= -0.641, p=0.0074; Mean arterial pressure (MAP): r= -0.6321, p=0.0086; Pulse Pressure (PP): r=0.5033, p=0.0468) in salt-sensitive but not salt-resistant patients (n=8). Furthermore, changes in blood pressure were positively correlated with increased NFKB2 (SBP: r=0.5276, p=0.0357; DBP: r=0.5366, p=0.0321; MAP: r=0.5872, p=0.0168), and TNF-α (PP: r=0.4505, p=0.0799) but not FAS gene expressions in salt-sensitive, but not salt-resistant patients (n=8).
Conclusion
These findings suggest that IER3 plays a role in salt-sensitive hypertension, possibly through the NFKB signaling pathway. The IER3 gene could serve as a valuable diagnostic marker for salt-sensitive hypertension or a novel treatment approach.