Key result
RGS5 knockout significantly reduced elevated post-surgery cytokine levels, including IL6 at 4 hours (34.3 vs 62.8 pg/mL, p<0.05), in an atheroprone mouse model subjected to surgical stress.
Why the study?
Perioperative myocardial infarction is driven by cytokine-induced plaque inflammation, and the role of RGS5 in the humoral perioperative stress response in vivo remained to be determined.
Does RGS5 knockout reduce the humoral inflammatory response in an atheroprone mouse model under surgical stress?
Does RGS5 knockout reduce the humoral inflammatory response in an atheroprone mouse model under surgical stress?
Answers are grounded in this paper and cite their sources.
RGS5 knockout significantly reduces elevated post-surgery cytokine levels in an atheroprone mouse model, suggesting a potential therapeutic target to prevent inflammation-related atherosclerotic cardiovascular events.
Background Perioperative myocardial infarction is a deadly complication for a million patients per year worldwide. Cytokines induce atherosclerotic plaque inflammation, thus vulnerability and progression. G-Protein Coupled Receptors (GPCR) and regulators of G-protein signalling, here RGS5, regulate signalling processes contributing to atherosclerosis. Cytokines involved in the inflammatory response to surgery were measured in a model of inducible RGS5 deficiency in atheroprone mice. Purpose To assess the role of RGS5 for the humoral perioperative stress response in vivo. Methods ApoE-/-CreERT2/ERT2RGS5flox/flox mice were fed a high fat diet for 7 weeks. Tamoxifen was administered (2mg ip/d for 5d) to induce RGS5 knockout (KO) before the animals were subjected to a perioperative double-hit (DBH) stress model, combining laparotomy with significant blood loss. Animals were sacrificed at 4- and 72-hours after DBH. RGS5 gene deletion and RNA expression were evaluated by real-time quantitative PCR. Plasma cytokine levels were measured using FACS based multiplex ELISA. Data were analyzed using Wilcoxon test using R in R studio. Results RGS5 DNA copies were reduced to 23% in tamoxifen-induced animals (TaqMan-gDNA-PCR) in bone marrow, leukocytes and spleen (ΔΔCT, mean±SD: 1.03±0.07 vs 0.24±0.12, p<0.001). RGS5-mRNA level in spleen was 45% (ΔΔCT: 1.42±1.24 vs 0.78±0.65, p<0.05) when compared to untreated controls. Plasma levels of IL6 increased significantly at 4h (median (CI95) in pg/mL, 3.7 (2.95-23.93) vs 62.8 (26.01-130.97), p<0.01) and then significantly decreased after 72h (5.5 (2.95-24.08), p<0.01) post-surgery. Similarly, CXCL1 levels significantly increased at 4h (in pg/mL, 54.76 (32.45-75.22) vs 124.9 (97.78-257.19), p<0.01) and then dropped back to baseline levels at 72h (40.9 (28.58-70.16), p<0.01) post DBH. RGS5 KO significantly reduced IL6 at 4h (in pg/mL, 34.3 (13.74-48.76), p<0.05) and CXCL1 at 72h (29.6 (19.73-41.20), p<0.05). Additionally, RGS5 KO significantly reduced the concentration of CCL11 at 72h (in pg/mL, 745.6 (366.9-964.4) vs 530.6 (259.8-675.3), p<0.05) post DBH. Similarly, CCL2 and TNF-α levels were reduced at 72h in Tamoxifen-treated mice. Conclusion RGS5 knockout was efficient with satisfactory penetrance in immune relevant tissues. Elevated post-surgery cytokine levels were significantly reduced by RGS5 KO indicating that lack of RGS5 in immune cells deregulates downstream signaling pathways of GPCRs which hampers cytokine release. RGS5 has a crucial role in immune cell activation and vascular inflammation and further research could deliver potential RGS5-targeted therapeutic strategies to prevent inflammation related atherosclerotic cardiovascular accidents.
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Anilkumar et al. (2025) studied Atherosclerosis and perioperative stress. Tamoxifen-induced RGS5 knockout vs. Untreated controls was evaluated on Plasma IL6 levels at 4 hours post-surgery (pg/mL) (p=<0.05). RGS5 knockout significantly reduced elevated post-surgery cytokine levels, including IL6 at 4 hours (34.3 vs 62.8 pg/mL, p<0.05), in an atheroprone mouse model subjected to surgical stress.
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