Abstract 15318: Global Deletion of P90 Ribosomal S6 Kinase Provides Cardiovascular Protection Against Age-Related Hypertension

Abstract

Background: Hypertension (HT) is highly prevalent and associated with significant mortality and morbidity among older individuals. Aging is associated with structural and functional remodeling of the vasculature, similar to blood vessel alterations observed in HT. We previously demonstrated that young adult global Rsk2 KO mice had more dilated mesenteric arteries (MAs), with reduced vessel tone, stiffness and RLC 20 phosphorylation, and significantly lower basal blood pressure compared to WT. However, it is unknown whether RSK2 plays a role in age-related HT. Hypothesis: Loss of RSK2 signaling in aged mice inhibits age-related- and L-NAME-induced HT, arterial stiffness, and vascular remodeling. Methods: Systolic blood pressure (SBP) measurements of >24-month-old global Rsk2 KO and WT males were performed daily for 2 weeks after 2 weeks of daily training using tail cuff manometry. Baseline echocardiographic (echo) parameters were measured. N(G)-Nitro-L-arginine-methyl ester (L-NAME) was administered (20 mg/kg/day) via drinking water to induce HT. Pressure myography studies assessed vascular reactivity and arterial stiffness in MAs isolated from Rsk2 KO and WT mice. Aorta and MAs were sectioned and stained to examine structural changes. Results: WT mice had a significantly higher mortality rate (63.6%) compared to Rsk2 KO (12.5%). Baseline SBP was also significantly higher in WT compared to KOs (123±10 vs. 99±12 mmHg, p < 0.001, n = 9/7). L-NAME elevated SBP in WT but not in KO mice (137±2 vs. 97±8 mmHg, p < 0.00001, n = 4/7). Although there were no differences in echo parameters, we observed a negative correlation between ejection fraction (EF) and SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6), but not in Rsk2 KO mice (p = 0.15, n = 7). Functional and histological studies in aged KO mice are ongoing to examine age-related changes in vascular reactivity and remodeling. Conclusion: Loss of RSK2 reduces BP levels in aged mice akin to young adult mice. Additionally, the hypertensive effects of L-NAME are absent in aged Rsk2 KO mice. Aged Rsk2 KO mice appear to be protected from cardiovascular effects associated with age-related HT. Therapeutic targeting of RSK2 could prove beneficial for reducing risk of cardiovascular diseases associated with HT in the elderly.