Hui, D. Y. | bioRxiv Science

bioRxiv2024

The human glucocorticoid receptor variant rs6190 promotes blood cholesterol and atherosclerosis

Elevated cholesterol poses cardiovascular risks. The glucocorticoid receptor (GR) harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene encoding the GR, rs6190, associated with increased cholesterol in women according to UK Biobank and All Of Us datasets. In SNP-genocopying mice, we found that the SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors respectively. In mice, the SNP was sufficient to elevate circulating cholesterol across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo liver knockdown of Pcsk9 and Bhlhe40. Also, corticosterone and tes-tosterone were protective against the mutant GR program in cholesterol and atherosclerosis in male mice, while the SNP effect was additive to estrogen loss in females. Remarkably, we found that the mutant GR program was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/625727v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@158e895org.highwire.dtl.DTLVardef@d9a2corg.highwire.dtl.DTLVardef@104e6bcorg.highwire.dtl.DTLVardef@c87160_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

Prefrontal Cortex Regulates Chronic Stress-Induced Cardiovascular Susceptibility

The medial prefrontal cortex (mPFC) is necessary for appropriate appraisal of stressful information, as well as coordinating visceral and behavioral processes. However, prolonged stress impairs mPFC function and prefrontal-dependent behaviors. Additionally, chronic stress induces sympathetic predominance, contributing to health detriments associated with autonomic imbalance. Previous studies identified a subregion of rodent prefrontal cortex, infralimbic cortex (IL), as a key regulator of neuroendocrine-autonomic integration after chronic stress, suggesting that IL output may prevent chronic stress-induced autonomic imbalance. In the current study, we tested the hypothesis that the IL regulates hemodynamic, vascular, and cardiac responses to chronic stress. To address this hypothesis, a viral-packaged siRNA construct was used to knockdown vesicular glutamate transporter 1 (vGluT1) and reduce glutamate packaging and release from IL projection neurons. Male rats were injected with a vGluT1 siRNA-expressing construct or GFP control into the IL and then remained as unstressed controls or were exposed to chronic variable stress (CVS). IL vGluT1 knockdown increased heart rate and mean arterial pressure (MAP) reactivity, while CVS increased chronic MAP only in siRNA-treated rats. In a separate cohort, CVS and vGluT1 knockdown interacted to impair both endothelial-dependent and endothelial-independent vasoreactivity ex vivo. Furthermore, vGluT1 knockdown and CVS increased histological markers of fibrosis and hypertrophy. Thus, knockdown of glutamate release from IL projection neurons indicates that these cells are necessary to prevent the enhanced physiological responses to stress that promote susceptibility to cardiovascular pathophysiology. Ultimately, these findings provide evidence for a neurobiological mechanism mediating the relationship between stress and poor cardiovascular health outcomes.\n\nClinical perspectiveWhat is new? O_LIKnockdown of glutamate release from infralimbic cortex increases heart rate and arterial pressure reactivity\nC_LIO_LIDecreased infralimbic glutamate output leads to vascular dysfunction after chronic stress\nC_LIO_LIThese functional changes associate with histological indicators of cardiac hypertrophy, as well as vascular hypertrophy and fibrosis\nC_LI\n\nWhat are the clinical implications? O_LIThese studies provide a neurobiological mechanism that may account for the link between long-term stress and increased cardiovascular disease risk\nC_LI

neuroscience↗