The Potential Impact of Succinic Acid Treatment on Age Associated Vascular and Vascular Mitochondrial Dysfunction

Abstract

A decline in vascular function is associated with aging. While the age‐related vascular dysfunction is multifactorial, vascular mitochondrial dysfunction is thought to contribute. Succinic acid (SA) has been shown to improve mitochondrial function by increasing mitochondrial biogenesis, though the vascular effects of SA are not well known.PURPOSETo determine the effect of SA treatment on vascular function of young and old mice.METHODSVascular function was measured in the aorta of 32 mice (15 young, 17 aged; 7 and 9 treated with succinic acid (0.75 mg/ml in drinking water), respectively). Using a wire myograph and Phenylephrine (PE), Acetylcholine (ACh), Potassium Chloride (KCl), and Sodium Nitroprusside (SNP) concentration response curves were generated, with and without the nitric oxide synthase (NOS) inhibitor, L‐NAME. In vitro measurements of vascular mitochondrial function were performed using permeabilized tissue respirometry using a substrate inhibitor protocol.RESULTSACh‐induced vasorelaxation was reduced with aging (60±32 v. 37±34 %relaxation). This endothelium dependent vasorelaxation was largely NO‐mediated, in both young (60±32 v. – 2±7 %relaxation) and old (37±34 v. 8±21 %relaxation), control v. L‐NAME, respectively. The aortas of SA‐treated mice had impaired ACh‐induced vasodilation in both young (60±32 v. 38±16 %relaxation) and old (37±34 v. 27±11 %relaxation), vehicle v. SA, respectively. The ACh‐induced vasorelaxation in SA treated mice, while reduced, was abolished with L‐NAME, (38±16 v. −7±2 %relaxation) and old (27±11 v. −8±8 %relaxation), control v. L‐NAME, respectively. The endothelium independent SNP‐induced vasorelaxation was not different between young and old (113±18 v. 98±14 %relaxation). The SNP responses were not different between vehicle and SA in either young (113±18 v. 84±18 %relaxation) or old (98±14 v. 108±9 %relaxation), vehicle v. SA treated, respectively. SNP relaxation was unaffected by L‐NAME in either group. Complex II driven respiration vascular mitochondrial respiration was ~50% lower with age (3.6 v. 7.6 pmol/mg/s, old v. young), which was improved with SA in both groups, but more so in the old (5.8 v. 2.2 Δpmol/mg/s, old v. young). Respiratory control ratio was not different between groups (1.47 vs. 1.43, old v. young), but tended to decrease with SA treatment (1.11 vs. 1.24, old v. young).CONCLUSIONSuccinic Acid reduces endothelium dependent vasorelaxation in both young and old mice, which appears to be due, at least in part, to reduced NO bioavailability. While SA appears to restore age‐related complex II mitochondrial dysfunction, it might come at a cost of reduced respiratory control ratio, perhaps increasing ROS production and abrogating endothelium derived NO. SA, an FDA approved compound, which has been used as an adjuvant therapy and is also often used in drug and food formulations, should be reconsidered given the potential effects of SA on the vasculature.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.