Abstract MP39: Autophagy Regulates β-hydroxybutyrate Synthesis To Prevent High-salt Induced Vascular Damage

Abstract

Overconsumption of dietary salt is unequivocally linked with end organ damage. We have recently observed that a high salt (HS) diet induces liver dysfunction in the form of impaired synthesis of ketone body, β-hydroxybutyrate (βOHB), in Dahl salt-sensitive rats. However, the molecular mechanisms as to why βOHB is decreased after consuming a HS diet remains unknown, as well as if it contributes to vascular dysfunction. We hypothesized that a HS diet (2%) for 8 weeks would decrease systemic levels of βOHB in Dahl salt-resistant (R) rats and this would be associated with endothelial dysfunction. Furthermore, reconstitution of βOHB bioavailability by giving 1,3-Butanediol (1,3-BD; 20% v/v ) in the drinking water would improve endothelial function in HS fed Dahl R. As hypothesized, a HS diet decreased serum concentration (mM) of βOHB [Low salt (LS), non-fasting (NF): 0.31±0.02 vs. fasting (F): 0.96±0.04*; HS, NF: 0.33±0.02 vs. F: 0.77±0.04*#, *p<0.05 vs. NF, #p<0.05 vs. LS-F]. A HS diet decreased the sensitivity of isolated mesenteric resistance arteries (MRA) to acetylcholine (ACh), and 1,3-BD treatment prevented this endothelial dysfunction (LogEC50, Dahl R-LS: -7.35±0.05 vs. Dahl R-HS: -7.19±0.07* vs. Dahl R-HS+1,3-BD: -7.42±0.10, p<0.05). Furthermore, when MRA were incubated with indomethacin, only Dahl R-HS presented with a decreased sensitivity to ACh (LogEC50, HS: -7.19±0.07 vs. HS+indomethacin: -7.66±0.08*, p<0.05), indicating that 1,3-BD treatment decreased cyclooxygenase-induced vascular inflammation (LogEC50, 1,3-BD -7.42±0.10 vs. 1,3-BD +indomethacin: -7.61±0.09, p>0.05). Evolutionarily, autophagy functions to mobilize nutrients in times of starvation, including ketone bodies such as βOHB. Therefore, we hypothesized that inhibition of autophagy would decrease βOHB. Treatment with lysosomal alkalizer chloroquine (CQ), impeded the starvation-induced increase in βOHB (NF: 0.38±0.02 vs. F: 1.11±0.09* vs. F+CQ: 0.78±0.19*#, *p<0.05 vs NF, # p<0.05 vs F). In summary, these data reveal that a HS diet decreases liver-derived βOHB, independent of high blood pressure, and is protective against HS-induced vascular damage. We suggest that autophagy could be a novel mechanism underlying the vascular protective effects of βOHB.