Exercise intervention attenuates hyperhomocysteinemia-induced aortic endothelial oxidative injury by regulating SIRT1 through mitigating NADPH oxidase/LOX-1 signaling

Abstract

Coronary artery disease (CAD) is a critical cardiovascular disease and a cause of high morbidity and mortality in this world. Hyperhomocysteinemia (HHcy) has been suggested as a risk factor for CAD. In addition, SIRT1 (sirtuin 1) has been reported to play a protective role in a variety of diseases, especially in the cardiovascular system. The main purpose of this study was to investigate the effects of exercise training on apoptosis and inflammation in HHcy animals. We also tested whether exercise protected against Hhcy-induced dysfunction of endothelium through modulation of SIRT1. C57BL mice (8 in each group) were fed with or without 1% L-methionine (w/w) in water for 4 months to induce HHcy. We found that Hhcy repressed SIRT1 and AMPK expression and increased NADPH oxidase activity. Plasma MDA, endothelium LOX-1 and p-p38 were up-regulated by Hhcy induction. NF-κB and it downstream molecules were activated under Hhcy situation, thereby promoting pro-inflammatory responses. Moreover, we also reported that Hhcy caused endothelium apoptosis involving Akt inhibition and mitochondria-dependent apoptotic pathways. Exercise training significantly protected against endothelium from Hhcy caused oxidative injuries. In addition, EX527 (SIRT1 inhibitor) reduced the therapeutic effects by exercise. Our results had indicated that exercise training prevent the development of atherosclerosis through SIRT1 activation and oxidative stress inhibition under Hhcy situation.

Picroside II attenuates hyperhomocysteinemia‐induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis

“…In endothelial cells, NADPH oxidase is identified as a major source of oxidative stress . Consistent with previous reports, the present study demonstrated that HHcy increased NADPH oxidase activation, lipid peroxidation and MDA elevation, and markedly decreased the activity of antioxidant enzymes, CAT and SOD. Our results also shown a marked reduction in HHcy‐induced elevation of ROS, MDA and NADPH oxidase activation after pretreatment with P‐II.…”

“…SIRT1, an important anti‐atherosclerosis molecule, protects the cardiovascular system from degeneration and oxidative injuries . Previous reports have suggested that SIRT1 activation is an effective approach to manage HHcy‐induced oxidative stress, and SIRT1 decreased the LOX‐1 expression level and NF‐κB activation . This statement is similar to our findings in the present study, as shown in Figures B and C, Hcy decreased SIRT1 expression significantly.…”

“…OxLDL, angiotensin II or other pro‐inflammatory events have been reported to activate LOX‐1 expression . Recently, several studies have reported a link between LOX‐1 and HHcy‐induced endothelial dysfunction . LOX‐1 up‐regulation by HHcy stimulates endothelial proinflammatory cytokines production and generation of superoxide radicals, consequently leading to cell apoptosis .…”

Folic Acid Can Reduce Hyperhomocysteinemia-induced Vascular Damage by Immune/Inflammatory Response in Spontaneously Hypertensive Rats

“…We also analyzed and selectively measured indicators for oxidative stress and in ammation in the blood circulation of HHcy-associated hypertensive rats and found that compared with SHRs, HHcy-associated hypertensive rats manifested higher levels of MDA, a serum oxidative product (P = 0.004), and lower levels of SOD, a serum antioxidant molecule (P = 0.000), suggesting that HHcy is associated with increased oxidative stress, which is in line with the pathogenic phenomena that Guo G [7] and Chan S [8] observed in HHcy. Previous studies also demonstrated that in ammatory indicators such as C-recreative protein [11] and the neutrophil/lymphocyte ratio [10] were signi cantly higher in patients with HHcy, which suggested that immunoin ammation did participate in the pathogenesis of hypertension associated with HHcy.…”

“…Patients of hypertension associated with HHcy have a higher incidence of vascular events and disability [5] than those of pure hypertension, suggesting that HHcy can aggravate vascular in ammation in hypertension. Previous studies indicate that HHcy can decrease endothelium-dependent and blood ow-mediated vasodilation [6] , increase oxidative stress [7][8][9] and in ammatory reactions [10,11] , and is closely related to the thickening of the arterial intima-media [12] and intravascular thrombosis [13] . HHcy is the abnormal aggregation of Hcy that is an intermediate product linking methionine metabolism and transsulfuration [14] in the body.…”