Effect of angiotensin II on energetics, glucose metabolism and cytosolic NADH/NAD and NADPH/NADP redox in vascular smooth muscle

Abstract

Angiotensin II (AII) is a neurohormone and contractile agonist of vascular smooth muscle that has been shown to be involved in the pathogenesis of vascular disease, which may be partially caused by its effect on oxidant stress. Energy metabolism was examined in pig carotid arteries treated with AII, because the activity of pathways of intermediary metabolism of glucose determines the status of cytosolic NADH/NAD and NADPH/NADP redox, factors which are involved in oxidant stress. Contractile responses to AII were characterized by an increase in isometric force followed by a gradual decline to near-basal levels. Despite contractile activation, no change in glycolysis, lactate production, glucose oxidation, fatty acid oxidation, O2 consumption, glycogen content or high-energy phosphates was detected when compared to resting unstimulated arteries. Paradoxically, total uptake of glucose was inhibited by AII. Treatment with diphenylene iodinium, an inhibitor of NAD(P)H oxidase and superoxide production, reversed the inhibition of glucose uptake and revealed the expected increase in glucose uptake and oxidation upon contractile activation of smooth muscle by AII. The intracellular [lactate]/[pyruvate] ratio was increased, reflecting an increase in cytosolic NADH/NAD redox, whereas NADPH/NADP redox was decreased by AII. No change in NADPH/NADP redox was observed when membrane depolarization with K+ was used as the contractile agent. It is concluded that the pattern of force generation, metabolism and energetics of AII-stimulated contraction are significantly different from that of other contractile agonists. Most notably AII inhibited glucose uptake. NAD(P)H oxidase and/or attendant superoxide may play a role in modulating glucose metabolism. AII induces opposite changes in NADH/NAD redox and NADPH/NADP redox, which may have important consequences for oxidant stress.

Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH

“…The cytosolic pool of NADP(H) seems to be significantly reduced in most cellular systems that have been studied, whereas the cytosolic NAD(H) pool seems to be highly oxidized in most cells under baseline-type conditions (19,80). Recent studies are consistent with vascular smooth muscle having cytosolic redox control mechanisms that are regulated in a manner similar to other cellular systems that have been previously characterized (12). The mitochondrial pool of NAD(H) is thought to be significantly reduced by the flow of substrates (pyruvate and fatty acids) into the Krebs cycle, but the redox status of this system appears to be dynamically regulated.…”

The Redox State of Transglutaminase 2 Controls Arterial Remodeling

“…More detailed studies have revealed that the redox balance is further controlled at the subcellular level [42]–[44]. In addition, the redox state of proteins can be individually regulated [45]. The cell-permeable reductant DTT that we used is known to activate in situ transamidation without affecting other TG2 functions [46].…”

The Redox State of Transglutaminase Controls Arterial Remodeling

“…More detailed studies have revealed that the redox balance is further controlled at the subcellular level [42][43][44]. In addition, the redox state of proteins can be individually regulated [45]. The cell-permeable reductant DTT that we used is known to activate in situ transamidation without affecting other TG2 functions [46].…”