Role of NLRP3-Mediated Inflammation on Cardiac Remodeling in a Physiological Model of Salt Sensitive Hypertension

Background: Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, with hypertension (HTN) being the third most prevalent form of CVD. Indeed, the incidence of HTN in US adults is nearly 122.4 million (46.7%), and prevalence is greater in men vs women until ~64 yrs. Thereafter, HTN prevalence is similar or greater in aged women vs aged men. End organ effects of HTN include left ventricle hypertrophy (LVH). However, the influence of NLRP3 inflammasome-mediated inflammation on LVH in HTN is still not fully elucidated. We hypothesized that NLRP3 knock down reduces inflammation and cardiac remodeling associated with salt-sensitive HTN. Methods: CRISPR-Cas9 was used to delete 14 base pairs in exon 1 of the NLRP3 gene in Dahl salt sensitive (DAHL/SS) rats, producing male and female NLRP3 knock out (KO) rats. Wildtype (WT) and KO were fed a low salt diet (Tekland 7034, NaCl 0.1%) ad libitum to delay the onset of severe HTN. Rats were studied at two different time points, ≤130 days of age vs ≥150 days of age. LV weight (LVW) was normalized to right tibial length (RTL) and used to assess LVH (LVW/RTL). Systolic blood pressure (SBP) was acquired via tail-cuff plethysmography after a 5-day adaptation period. To assess inflammation status complete blood count (CBC) was assessed using plasma obtained via cardiac puncture and IL-18 levels by ELISA. Data are presented as mean ± SEM. Results: LVW/RTL was significantly increased in the KO rats compared to WT (KO, n=43: 236.2 ± 6.12mg/cm; WT, n=23: 221.2 ± 6.67mg/cm; p<0.01), with a significant sex*age interaction (p<0.02) where greater increases were observed in older males. SBP increased at ≥150 days of age (≥150 days, n=9: 201 ± 4.34mmHg; ≤130 days, n=8: 154.5 ± 7.76mmHg; p<0.001) independent of sex (female, n=10: 180.2 ± 10.70mmHg; male, n=7: 177.6 ± 8.65mmHg; p=0.50). White blood cells (WBC) and neutrophils (NE) were increased at ≥150 days of age (p<0.01), with males having greater WBC and NE (p<0.05) than females. WT rats had increased lymphocyte proliferation (p<0.05) with greater increases at ≥150 days of age (p<0.01), and males were observed to had greater presence of lymphocytes than females (p<0.01). A similar pattern was observed in red blood cells (RBC), and hemoglobin (Hb). Whereas hematocrit (HCT) was greater in males vs females (p<0.05), a significant genotype*age interaction was observed (p<0.05), with a marked increase at ≥150 days regardless of genotype. IL-18 levels were similar across groups (KO, n=13: 100.2 ± 20.8pg/uL; WT, n=11: 131.8 ± 70.17pg/uL; p=0.6217) (males, n=11: 68.81 ± 19.35pg/uL; females, n=13: 153.5 ± 58.62pg/uL; p=1801) (≤130 days, n=7: 75.79 ± 31.53pg/uL; ≥150 days, n=17: 130.7 ± 45.51pg/uL; p=0.4497). Conclusion: Contrary to our preliminary hypothesis, LV mass was greater in the NLRP3 KO vs WT rats, concomitant with increased SBP and inflammatory markers. Our data suggests a previously unidentified protective role for the NLRP3 on cardiac growth in salt sensitive hypertension but requires additional investigation. This work was supported by NIH R21 AG070723-01 and NIH T32 training program (T32DK120509) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.