Nitric oxide inhibits endothelial cell apoptosis by inhibiting cysteine‐dependent SOD1 monomerization

Abstract

Endothelial cell apoptosis is an important pathophysiology in many cardiovascular diseases. The gasotransmitter nitric oxide (NO) is known to regulate cell survival and apoptosis. However, the mechanism underlying the effect of NO remains unclear. In this research, by targeting cytosolic copper/zinc superoxide dismutase (SOD1) monomerization, we aimed to explore how NO inhibited endothelial cell apoptosis. We showed that treatment with the NO synthase (NOS) inhibitor nomega‐nitro‐l‐arginine methyl ester hydrochloride (L‐NAME) significantly decreased the endogenous NO content of endothelial cells, facilitated the formation of SOD1 monomers, inhibited dismutase activity, and promoted reactive oxygen species (ROS) accumulation in human umbilical vein endothelial cells (HUVECs); by contrast, supplementation with the NO donor sodium nitroprusside (SNP) upregulated NO content, prevented the formation of SOD1 monomers, enhanced dismutase activity, and reduced ROS accumulation in L‐NAME‐treated HUVECs. Mechanistically, tris(2‐carboxyethyl) phosphine hydrochloride (TCEP), a specific reducer of cysteine thiol, increased SOD1 monomer formation, thus preventing the NO‐induced increase in dismutase activity and the decrease in ROS. Furthermore, SNP inhibited HUVEC apoptosis caused by the decrease in endogenous NO, whereas TCEP abolished this protective effect of SNP. In summary, our data reveal that NO protects endothelial cells against apoptosis by inhibiting cysteine‐dependent SOD1 monomerization to enhance SOD1 activity and inhibit oxidative stress.

Quantum Sensing for Detection of Zinc‐Triggered Free Radicals in Endothelial Cells

“…Therein, the largest level of RNS, such as NO ● , was detected, though the formation of ROS diminished, either barely (4‐h incubation) or considerably (24‐h incubation). Since nitric oxide promotes dismutase activity in HUVECs, [ 64 ] we speculate that the protective properties of SOD1 might have weakened as a result of zinc excess and simultaneous overproduction of various free radicals provoking nuclei fragmentation, cell shrinkage, and bleb formation.…”

The Role of Gasotransmitter-Dependent Signaling Mechanisms in Apoptotic Cell Death in Cardiovascular, Rheumatic, Kidney, and Neurodegenerative Diseases and Mental Disorders

“…In addition, NO induces the opening of mitochondrial K + -ATP channels and inhibits Ca 2+ overload ( Figure 5 ) [ 72 ]. In addition, a mechanism has recently been described in which NO protects endothelial cells from oxidative stress-induced apoptosis by inhibiting cysteine-dependent superoxide dismutase (SOD1) monomerization and thus blocking its inactivation [ 73 ].…”

Big Things, Small Packages: An Update on Microalgae as Sustainable Sources of Nutraceutical Peptides for Promoting Cardiovascular Health

“…The eNOS is one interesting pro‐target for protection against hypertension and cardiovascular diseases, as it produces nitric oxide (NO), which protects vascular integrity by preventing platelet aggregation, and smooth muscle proliferation. [ 46 ] NO is usually produced from the oxidation of the l ‐arginine to l ‐citrulline by eNOS in the presence of the 5,6,7,8‐tetrahydro‐l‐biopterin (BH 4 ) cofactor. Oxidative stress, such as the abundance of superoxide radical in the cells, mops up the vasoprotective NO to produce peroxynitrite (ONOO − ), which then diminishes the BH 4 cofactors.…”