Hyperhomocysteinemia (HHcy) has been recognized as an independent risk factor for atherosclerosis for more than 30 years, but the mechanisms by which HHcy leads to atherosclerosis are not well fully understood. In this review, we will summarize the immunoregulatory effects of homocysteine on cardiovascular diseases from humoral immunity, monocyte/macrophage and T lymphocyte activity. Homocysteine can induce chemokine and cytokine secretion in monocytes and T lymphocytes and also directly stimulate B lymphocyte proliferation and IgG secretion. In addition, the cellular mechanisms that may explain the pro-inflammatory effect of HHcy are included. Homocysteine may directly or indirectly lead to oxidative stress or endoplasmic reticulum (ER) stress. Elevated levels of homocysteine also decrease the bioavailability of nitric oxide and modulate the levels of other metabolites including S-adenosyl methionine and S-adenosyl homocysteine which may result in cardiovascular diseases.
Animals ; Atherosclerosis ; Cardiovascular Diseases ; immunology ; physiopathology ; Homocysteine ; physiology ; Humans ; Hyperhomocysteinemia ; complications ; Macrophages ; Nitric Oxide ; Oxidative Stress

Arteriosclerosis and its complications, such as heart attack and stroke, are the major causes of death in developed countries. It was believed that age, hyperlipidemia, hypertension, diabetes and smoking are common risk factors for cardiovascular disease. In addition, overwhelming clinical and epidemiological studies have identified homocysteine (Hcy) as a significant and independent risk factor for cardiovascular disease. In healthy individuals, plasma Hcy is between 5 and 10 micromol/L. One cause of severe hypehomocys- teinemia (HHcy) is the deficiency of cystathionine beta-synthase (CBS), which converts Hcy to cystathionine. CBS homozygous deficiency results in severe HHcy with Hcy levels up to 100 to 500 micromol/L. Patients with severe HHcy usually present with neurological abnormalities, premature arteriosclerosis. It has been reported that lowering plasma Hcy improved endothelial dysfunction and reduced incidence of major adverse events after percutaneous coronary intervention. The mechanisms by which Hcy induces atherosclerosis are largely unknown. Several biological mechanisms have been proposed to explain cardiovascular pathological changes associated with HHcy. These include: (1) endothelial cell damage and impaired endothelial function; (2) dysregulation of cholesterol and triglyceride biosynthesis; (3) stimulation of vascular smooth muscle cell proliferation; (4) thrombosis activation and (5) activation of monocytes. Four major biochemical mechanisms have been proposed to explain the vascular pathology of Hcy. These include: (1) autooxidation through the production of reactive oxygen species; (2) hypomethylation by forming SAH, a potent inhibitor of biological transmethylations; (3) nitrosylation by binding to nitric oxide or (4) protein homocysteinylation by incorporating into protein. In summary, our studies, as well as data from other laboratories support the concept that Hcy is causally linked to atherosclerosis, and is not merely associated with the disease. Although folic acid, vitamin B12 and B6 can lower plasma Hcy levels, the long-term effects on cardiovascular disease risk are still unknown and judgments about therapeutic benefits await the findings of ongoing clinical trials.
Animals ; Atherosclerosis ; etiology ; physiopathology ; Cystathionine beta-Synthase ; deficiency ; genetics ; Homocysteine ; metabolism ; Humans ; Hyperhomocysteinemia ; complications ; physiopathology ; Reactive Oxygen Species ; metabolism

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Cognitive Dysfunction/complications* ; DNA Methylation ; Homocysteine/metabolism* ; Hyperhomocysteinemia/metabolism* ; Rats ; Stress, Psychological/physiopathology*

BACKGROUNDThe high blood homocysteine (Hcy) levels found in patients with hyperhomocysteinemia (HHcy) have been implicated in an increased risk of cardiovascular disease morbidity and mortality in end-stage renal disease (ESRD). This study investigated the association of HHcy with progression of IgA nephropathy.

METHODSWe analyzed 108 participants newly diagnosed with IgA nephropathy between August 2005 and August 2007 in the Department of Nephrology, Chinese People's Liberation Army General Hospital. The association between clinicopathological factors and the Hcy levels were analyzed by Logistic regression and those with ESRD risk were analyzed by Cox regression.

RESULTSPatients were aged (35.71 ± 10.73) years and included 45.71% women and 12.04% patients with HHcy. In multivariate Logistic regression analysis, HHcy was associated with arterial lesions (OR 2.60; 95% CI 1.55 ± 4.34; P < 0.001) even when age, body mass index, estimated glomerular filtration rate, mean arterial pressure, and initial proteinuria were taken into account. Mean follow-up was (67.37 ± 16.21) months. HHcy was also associated with worse ESRD-free survival (HR 4.71; 95% CI 1.45 to 15.31; P = 0.010).

CONCLUSIONHHcy is associated with the risk of intrarenal arterial lesions and may be useful for estimating the prognosis of IgA nephropathy.

Adult ; Body Mass Index ; Female ; Glomerular Filtration Rate ; physiology ; Glomerulonephritis, IGA ; etiology ; physiopathology ; Humans ; Hyperhomocysteinemia ; complications ; physiopathology ; Logistic Models ; Male ; Middle Aged ; Retrospective Studies

Hyperhomocyst(e)inemia is an established risk factor for atherosclerosis. We performed this study to identify the correlating variables and risk factors for atherosclerosis, as measured by the atherosclerotic score (AS), and to determine the relative risk for cardiovascular disease in relation to plasma homocyst(e)ine levels in patients on chronic hemodialysis. We evaluated and measured 61 patients on chronic hemodialysis for clinical and biochemical parameters including atherosclerotic score (AS) and plasma homocyst(e)ine. We divided patients into high and low groups, first, by the mean AS, and second, by the median value of plasma total homocyst(e)ine levels. Then we compared the variables between the two groups. Out of the 61 patients, the median plasma total homocyst(e)ine level was 24.4 micromol/L (mean+/-SD, 27.7+/-17.4; range, 9.8-127.4 micromol/L), and the median AS was 5 (mean+/-SD, 6.2+/-2.8; range, 3-13) out of a possible 20 points. AS was significantly correlated with plasma total homocyst(e)ine levels (r=0.37) and age (r=0.67). Through multivariate analysis, plasma total homocyst(e)ine level and age were determined as significant risk factors for the high-AS group (p<0.05). However, plasma total homocyst(e)ine level did not correlate with age (p>0.05). Eighteen of the 61 patients, presented with cardiovascular disease until the present study, had an AS>6. Cardiovascular disease was found more often in the high-homocyst(e)ine group (>24.4 micromol/L) than in the low-homocyst(e)ine group (odds ratio, 9.3; 95% confidence interval, 2.3-37.4). Regardless of age, hyperhomocyst(e)inemia (especially homocyst(e)ine levels >24.4 micromol/L) is a risk factor that can be modified for the development of cardiovascular disease in patients on chronic hemodialysis.
Adolescence ; Adult ; Aged ; Arteriosclerosis/etiology* ; Chronic Disease ; Female ; Homocysteine/blood* ; Homocystine/blood* ; Human ; Hyperhomocysteinemia/physiopathology* ; Male ; Middle Age ; Renal Dialysis* ; Risk Factors

OBJECTIVETo detect the levels of nitric oxide synthetase (NOS) and carbon monoxide (CO) in the penile corpus cavernous of adult male Wistar rats with high homocysteine (Hhcy) and to explore the relationship of NOS and CO levels with erectile dysfunction.

METHODSTwenty Wistar rats were equally and randomly divided into a control and an Hhcy group and fed on normal diet and normal diet with 3.0% methionine respectively. Four weeks later, the levels of NOS and CO in the penile corpus cavernous were detected by ultraviolet spectrophotometry and that of serum homocysteine by the cycle enzyme method.

RESULTSCompared with the control group, the levels of NOS and CO in the penile corpus cavernous were significantly lower in the Hhcy group, (6.45 +/- 1.12) nmol/(g x min) vs (10.77 +/- 0.60) nmol/(g x min) and (10.60 +/- 0.92) micromol/L vs (13.36 +/- 0.44) micromol/L, while that of homocysteine was significantly higher, (22.32 +/- 1.65) micromol/L) vs (4.90 +/- 1.73) micromol/L.

CONCLUSIONFour-week diet with methionine can cause Hhcy and significantly decreased levels of NOS and CO in the penile corpus cavernous in Wistar rats. Hhcy is an independent risk factor of erectile dysfunction.

Animals ; Carbon Monoxide ; metabolism ; Homocysteine ; blood ; Hyperhomocysteinemia ; blood ; physiopathology ; Male ; Nitric Oxide Synthase ; metabolism ; Penis ; metabolism ; Rats ; Rats, Wistar ; Spectrophotometry, Ultraviolet

BACKGROUNDWhile hyperhomocysteinemia is associated with an increased risk of cardiovascular diseases, the effect of hyperhomocysteinemia on the vascular adventitia and vessel remodeling has not been clearly demonstrated. We investigated the effect of the hyperhomocysteinemia on adventitial hyperplasia and vascular remodeling following balloon injury in rats and the underlying mechanisms.

METHODSRats were fed with diet containing methionine for 4 weeks to increase plasma homocysteine before balloon injury. Vascular geometrical changes were assessed at different time points following balloon injury. The collagen deposition was determined by picrosirius red staining and immunohistochemical staining.

RESULTSWhen compared with normal diet group, moderate hyperhomocysteinemia in methionine diet group significantly exacerbated adventitial hyperplasia at day 7 and collagen deposition mainly in the adventitia at day 28 following balloon injury. The increased plasma homocysteine level significantly increased collagen deposition in the adventitia. There was a negative correlation (r = -0.698; P < 0.01) between the luminal area and the collagen content in the adventitia on day 28 following balloon injury. In cultured adventitial fibroblasts isolated from rat aorta, 100 micromol/L L-homocysteine (L-Hcy) significantly down-regulated matrix metalloproteinase-2 activity by 43% as determined by in vitro gelatin zymography (P < 0.05) and up-regulated the expression of collagen type I by 187% (P < 0.05) assessed by Western blotting.

CONCLUSIONSHyperhomocysteinemia exacerbated vascular constrictive remodeling by accelerated neointima formation and collagen accumulation in the adventitia. Increased collagen deposition may be the underlying mechanism.

Angioplasty, Balloon ; adverse effects ; Animals ; Carotid Arteries ; metabolism ; pathology ; physiopathology ; Catheterization ; adverse effects ; Collagen ; metabolism ; Diet ; Hyperhomocysteinemia ; etiology ; physiopathology ; Hyperplasia ; etiology ; Immunohistochemistry ; Male ; Methionine ; administration & dosage ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effect of vitamin B on treatment of hyperhomocysteinemia and endothelial dysfunction in renal-transplant recipients.

METHODSThirty-six stable hyperhomocysteinemic renal-transplant recipients were randomly assigned to vitamin treatment (group A, n = 18, folic acid 5 mg/d, vitamin B(6) 50 mg/d, B(12) 1000 microg/d) or controlled group (group B, n = 18) for 6 months. All subjects underwent assessment of levels for creatinine, creatinine clearance, average pressure, total cholesterol, triglyceride and fasting homocysteine. Endothelial function was evaluated using high-resolution vascular ultrasound.

RESULTSThe levels of homocysteine markedly decreased in group A [(13 +/- 4) micromol/L vs (20 +/- 5) micromol/L, t = 5.3, P < 0.01] after treatment, whereas no significant changes were observed in group B. In group A, endothelium dependent [(12 +/- 5)% vs (9 +/- 5)%, t = 2.9, P < 0.01] and independent [(18 +/- 4)% vs (12 +/- 5)%, t = 3.4, P < 0.01] vasodilatation responses significantly increased after treatment, no significant changes were observed in group B. Endothelium dependent [(9 +/- 6)%, t = 2.8, P < 0.01] and independent [(12 +/- 5)%, t = 3.5, P < 0.01] vasodilatation responses of group A were significantly lower than that of group B after treatment.

CONCLUSIONSVitamin B supplementation can reduce the levels of homocysteine and improve the endothelial function in hyperhomocysteinemic renal-transplant recipients.

Adult ; Drug Therapy, Combination ; Endothelium, Vascular ; drug effects ; physiopathology ; Female ; Folic Acid ; administration & dosage ; Humans ; Hyperhomocysteinemia ; drug therapy ; physiopathology ; Kidney Transplantation ; Male ; Middle Aged ; Treatment Outcome ; Vitamin B 12 ; administration & dosage ; Vitamin B 6 ; administration & dosage

OBJECTIVETo study the effect of Tongxinluo superfine (TXL) on experimental anginal model induced by Arginine Vasopressin in rats with endothelial dysfunction.

METHODFirst, the endothelial dysfunction rat model was made by methionine-induced hyperhomocysteinemia (HHcy). The thoracic aorta were excised, and acetylcholine (Ach)-induced endothelium dependent relaxation and sodium nitroprusside (SNP) induced endothelium-independent relaxation were measured. Total plasma homocysteine (Hcy) concentrations were measured with automated fluorescence polarization immunoassay (FPIA). Enzyme-linked immunosorbent assay (ELISA) was used to detect plasma von Willebrand factor (vWF) level. Plasma nitric oxide (NO) contents were assayed by method of nitrate reductase. Then, the rat model of collaterals contraction (model group) was established by AVP intravenous injection in rats with endothelial dysfunction and the S wave change (DeltaS) and T wave depression in Lead II ECG were used as the index of angina severity. The nitric oxide (NO) contents in serum and the expression of myocardium eNOS mRNA were measured.

RESULTAch (0. 1-1000 nmol L(-1))-induced endothelium dependent relaxation (EDR) of aortic rings was significantly decreased in HHcy group. The endothelium-independent relaxation induced by SNP (0.001-10 micromol L(-1)) was not significantly different between the two groups. Plasma homocysteine concentrations and vWF levels in rats treated with methionine were higher than those of control group, while NO contents were significantly decreased in HHcy group compared with control. The results showed that L-methionine intake induced hyperhomocysteinemia in rats. Impaired EDR, increased vWF and decreased NO suggested the exist of endothelial dysfunction. DeltaS of model group increased from 1 min to 5 min and T wave of model group depressed at 2 min compared with that of control after the administration of vasopressin (0.5 U kg(-1)). The intragastric administration of TXL inhibited vasopressin-induced S wave change at 4 min and 5 min and T wave depression from 30 s to 3 min after AVP injection. The NO contents in serum and the expression of myocardium eNOS mRNA of TXL group were increased compared with model group.

CONCLUSIONExperimental angina induced by AVP injection is more severe in rats with endothelial dysfunction. Tongxinluo Superfine can protect against collaterals contraction in rats maybe by increasing the NO contents in serum and the expression of myocardium eNOS mRNA.

Acetylcholine ; pharmacology ; Animals ; Aorta, Thoracic ; drug effects ; physiopathology ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacology ; Electrocardiography ; Endothelium, Vascular ; drug effects ; physiopathology ; Enzyme-Linked Immunosorbent Assay ; Hyperhomocysteinemia ; metabolism ; physiopathology ; In Vitro Techniques ; Male ; Myocardial Ischemia ; blood ; genetics ; physiopathology ; Myocardium ; metabolism ; pathology ; Nitric Oxide ; blood ; Nitric Oxide Synthase Type III ; biosynthesis ; genetics ; Nitroprusside ; pharmacology ; Plants, Medicinal ; chemistry ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Vasodilation ; drug effects ; Vasodilator Agents ; pharmacology ; von Willebrand Factor ; metabolism