Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.

Abstract

The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated the identity of the oxidases responsible for its production. Treatment of vascular smooth muscle cells with Ang II for 4 to 6 hours caused a 2.7 +/- 0.4-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. This superoxide appeared to result from activation of both the NADPH and NADH oxidases. NADPH oxidase activity increased from 3.23 +/- 0.61 to 11.80 +/- 1.72 nmol O2-/min per milligram protein after 4 hours of Ang II, whereas NADH oxidase activity increased from 16.76 +/- 2.13 to 45.00 +/- 4.57 nmol O2-/min per milligram protein. The NADPH oxidase activity was stimulated by exogenous phosphatidic and arachidonic acids and was partially inhibited by the specific inhibitor diphenylene iodinium. NADH oxidase activity was increased by arachidonic and linoleic acids, was insensitive to exogenous phosphatidic acid, and was inhibited by high concentrations of quinacrine. Both of these oxidases appear to reside in the plasma membrane, on the basis of migration of the activity after cellular fractionation and their apparent insensitivity to the mitochondrial poison KCN. These observations suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.

Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome

“…4 Angiotensin II stimulates the production of free radicals within the endothelial monolayer with subsequent increase of oxidative stress and development of endothelial dysfunction. 5,6 Moreover, local angiotensin II, synthesized in cavernosal tissue exerts direct effects on erectile function, as indicated by the termination of spontaneous erection by intracavernosal injection of angiotensin II. 7 Thus, inhibition of the renin-angiotensin system (RAS) may improve erectile function by inhibition of specific effects of angiotensin II in the corpus cavernosum, reduction of blood pressure and amelioration of endothelial function in the corpus cavernosum and the penile arteries.…”

Modulating atherosclerosis through inhibition or blockade of angiotensin

“…In response to angiotensin II, enzymes in the endothelium, smooth muscle, and fibroblasts that use nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH) substrates, or both, are activated and yield superoxide anion. [16][17][18][19][20] Therefore, we would expect superoxide production to increase when the local or systemic renin-angiotensin system (RAS) is activated-and increased vascular NADH/NADPH oxidase activity has been demonstrated in animal models of early atherosclerosis along with activation of the RAS. 21 When NADH/NADPH oxidase is activated, the amount of superoxide within the vascular wall increases, and atherosclerosis can progress.…”

“…Specifically, several proinflammatory cytokines and growth factors (tumor necrosis factor-alpha [TNF-␣], interleukin-1␤ [IL-1␤], and interferon-gamma [IFN-␥]) as well as angiotensin II activate membrane-bound NADPH-like oxidase activity in endothelial and vascular smooth muscle cells, resulting in superoxide anion production. 16,17,19,21 Superoxide and other free radicals promote LDL oxidation and degradation of NO. The ROS that are responsible for LDL oxidation also stimulate the synthesis of other vascular inflammatory products and adhesion molecules that include monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1).…”

Endothelial dysfunction, angiotensin-converting enzyme inhibitors and calcium antagonists

“…It is well known that angiotensin II stimulates the NADH/NAD(P)H oxidase of endothelial and smooth muscle cells. 25 Figure 1 shows the effects of highly specific tissular ACE inhibitors in restoring the balance on the endothelial production of NO and O − 2 . Recent evidence has shown that acute administration of calcium antagonists improves the abnormal coronary vasomotion response in hypertension, atherosclerosis and hypercholesterolaemia.…”