Zofenopril inhibits the expression of adhesion molecules on endothelial cells by reducing reactive oxygen species

Abstract

Hypertension and coronary artery disease are intimately connected. The migration of circulating monocytes into the subendothelial occurs through the expression of some adhesion molecules on endothelial cells. The nuclear factor (NF)-kappaB, a redox-sensitive element, plays a key role in adhesion molecule gene induction. In this study we have compared the effects of two different angiotensin converting enzyme (ACE) inhibitors, one possessing an active sulfhydryl group (zofenopril) and one lacking this group (enalapril) on the cellular redox state (monitored by measuring intracellular reactive oxygen species and thiol status), expression of adhesion molecules, and activation of NF-kappaB in human umbilical vein endothelial cells (HUVECs). Zofenoprilat, the active form of zofenopril, significantly and dose dependently reduced the intracellular reactive oxygen species (ROS) and superoxide formation induced by oxidized low-density lipoprotein (ox-LDL) (P <.001) and tumor necrosis factor-alpha (TNF-alpha) (P <.001). Enalaprilat, the active form of enalapril, was ineffective. Zofenoprilat but not enalaprilat also decreased the consumption of the intracellular GSH induced by ox-LDL (P <.01) and TNF-alpha (P <.01). Although zofenoprilat significantly and dose dependently reduced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin induced by ox-LDL (P <.01) and TNF-alpha (P <.01) on HUVECs, enalaprilat did not. Ox-LDL and TNF-alpha increased the activation of NF-kappaB and the preincubation of HUVECs with zofenoprilat, but not with enalaprilat, dose dependently reduced its activation (P <.001). The conclusion is that the sulfhydryl (SH)-containing ACE inhibitors may be useful in inhibiting foam cell formation and thus slow the development of atherosclerosis.

Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients

“…The mean age of the patients was 41.6±2.6 (range [36][37][38][39][40][41][42][43][44][45][46] EPCs increased during the follow-up with no statistical differences between treatment groups.…”

“…[31][32] Sulfhydryl ACE inhibition stimulates the NO activity and decreases oxidative stress in human endothelial cells [33] and in patients with essential hypertension. [21] Zofenopril increases NO production in endothelium, decreases atherosclerotic development, and reduces reactive oxygen species, [34][35][36][37] as well as susceptibility to oxidation of plasma lowdensity lipoproteins (LDL) and formation of oxidation-specific epitopes in the arterial wall and atherogenesis in apolipoprotein E knockout mice. [35] The meaning of NOx levels would be qualitatively rather than quantitatively.…”

Effects of Antihypertensive Drugs on Alcohol-Induced Functional Responses of Cultured Human Endothelial Cells

“…Some angiotensin-converting enzyme (ACE) inhibitors improve the endothelial response in epicardial, renal, and subcutaneous vessels, but are ineffective in the forearm vessels of hypertensive patients (32). Zofenoprilat is a sulfhydryl-containing ACE inhibitor that has already been shown to decrease oxidative stress both in vitro (17,33) and in vivo (34), suggesting that this molecule has hydroxyl-radical scavenging properties. In the present study, zofenoprilat decreased the consumption of intracellular glutathione induced by ethanol and the production of malondialdehyde by endothelial cells.…”

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

“…Likewise this, but comparing two ACEis: enalapril and zofenopril [227], authors tested the effectiveness of these two molecules on the cellular redox state (monitored by measuring intracellular reactive oxygen species and thiol status), expression of adhesion molecules, and activation of NF-kB in human umbilical vein endothelial cells (HUVECs). Zofenoprilat, the active form of zofenopril, significantly and dose dependently reduced the intracellular ROS and superoxide formation induced by oxidized low-density lipoprotein (ox-LDL) (P <.001) and TNF-alpha (P <.001).…”