Diallyl disulfide and diallyl trisulfide protect endothelial nitric oxide synthase against damage by oxidized low‐density lipoprotein

Abstract

Garlic is viewed as an effective health food against atherosclerosis. In this study, we examined whether diallyl disulfide (DADS) and diallyl trisulfide (DATS) protect endothelial nitric oxide synthase (eNOS) activation against oxidized LDL (ox-LDL) insult and through what mechanism. We found that DADS and DATS reversed the suppression of eNOS Ser1177 phosphorylation by ox-LDL, and wortmannin abolished the reversal by DADS and DATS. Similarly, the inhibition of cellular cGMP and nitric oxide production by ox-LDL was reversed by DADS and DATS (p<0.05). This increase in nitric oxide bioavailability by the allyl sulfides was attenuated by wortmannin. Immunoprecipitation assay revealed that DADS and DATS preserved the interaction of eNOS with caveolin-1 in the membrane. In addition, DADS and DATS suppressed the reduction of the cellular eNOS protein content by ox-LDL. When cycloheximide was added to block protein synthesis, DADS and DATS suppressed eNOS protein degradation similarly to that noted by MG132. Ox-LDL increased chymotrypsin-like proteasome activity, and this increase was inhibited by the allyl sulfides and MG132 (p<0.05). These results suggest that DADS and DATS protect eNOS activity against ox-LDL insult. This protection can be attributed partly to their mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and prevention of eNOS degradation.

The polysulfide diallyl trisulfide protects the ischemic myocardium by preservation of endogenous hydrogen sulfide and increasing nitric oxide bioavailability

“…Furthermore, DATS has been shown to protect eNOS function against damage by oxidized low-density lipoprotein as well as to protect endothelial cells and increase eNOS expression and NO bioavailability after coronary injury (15,18). We investigated the extent of eNOS phosphorylation and NO metabolites levels in DATS-treated mouse hearts and observed an increase in eNOS phosphorylation at Ser 1177 , the activating phosphorylation site, starting at 30 min and continuing to 2 h. However, we did not see a change in phosphorylation at Thr 495 , the inhibiting phosphorylation site.…”

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

“…The protective effects of garlic against renal, hepatic, cardiac, cerebral, and pulmonary ischemia/ reperfusion injury are also well known (Sener et al 2007). Garlic-derived compounds such as DADS and DATS can attenuate the deleterious effects of oxidized LDL on nitric oxide production (Lei et al 2010) and attenuate myocardial ischemia/reperfusion in mice (Predmore et al 2010). DADS is also known to inhibit 3-hydroxy-3-methylglutaryl-CoA and thus may be a potential antihyperlipidemic agent (Rai et al 2009).…”

Hydrogen sulfide in signaling pathways

“…S-allylcysteine exhibits a range of cardioprotective actions, which include the reduction of blood platelet aggregation [122,123,127]. It has known that di-/tri-sulfide modulates the interaction between leukocyte and endothelial cells through the protein kinase A and enhances eNOS phosphorylation and stability [10,[127][128][129]. Giustarini et al [130] have demonstrated that H 2 S-releasing aspirin (ACS14) modulates thiol homeostasis.…”