Elsevier

Atherosclerosis

Volume 158, Issue 2, October 2001, Pages 399-405
Atherosclerosis

Correlation of plasma homocysteine and mitochondrial DNA content in peripheral blood in healthy women

https://doi.org/10.1016/S0021-9150(01)00436-1Get rights and content

Abstract

Hyperhomocysteinemia is an independent risk factor of cardiovascular disease and associated with insulin resistance, although their causal relationship remains unclear. A previous report has shown that high concentration of homocysteine damages mitochondrial gene expression, function and structure. As we found recently, the mitochondrial DNA (mtDNA) contents are inversely correlated with insulin resistance parameters. Thus there is possibility that plasma total homocysteine (tHcy) level is somewhat correlated with mtDNA content. Sixty healthy women (mean age 40.3±20.9 yr, range 18–78 yr) were recruited to investigate the correlation of plasma tHcy level and mtDNA content in peripheral blood. A significant negative correlation was found between plasma tHcy levels and mtDNA content (r=−0.507, P<0.01). Plasma tHcy and mtDNA content have an independent effect on each other and on insulin resistance (HOMA-insulin resistance (IR) score) respectively in multiple regression model. Plasma tHcy showed positive correlations with age (r=0.407), W/H ratio (r=0.370), total cholesterol (r=0.338), LDL-cholesterol (r=0.317) and insulin resistance (HOMA-IR score) (r=0.261); and a negative correlation with folate (r=−0.273). MtDNA content showed negative correlations with age (r=−0.407), BMI (r=−0.440), W/H ratio (r=−0.659), SBP (r=−0.350), total cholesterol (r=−0.340), triglyceride (r=−0.376), LDL-cholesterol (r=−0.349), fasting plasma insulin (r=−0.483), and insulin resistance (HOMA-IR score) (r=−0.423); and a positive correlation with folate (r=0.299). In this study, there was a significant inverse correlation between plasma tHcy level and mtDNA content. Further study will be warranted to elucidate the mechanism by which two factors are associated.

Introduction

Hyperhomocysteinemia has been reported as an independent risk factor for atherosclerosis in coronary, cerebral, and peripheral vascular disease [1]. The moderately high levels of plasma total homocysteine (tHcy) were associated with subsequent risk of myocardial infarction [2]. Plasma tHcy level was significantly higher in stroke patients than controls and the risk of stroke increased with increase in the concentrations of tHyc [3]. Although high level of tHyc is associated with endothelial dysfunction and injury, physiological mechanisms underlying this remains unclear.

High level of plasma homocysteine is known to exert its effects through a mechanism involving oxidative damage [4], [5]. In vitro, homocysteine is rapidly auto-oxidized when added to plasma, forming homocystine, homocysteine-mixed disulfides, and homocysteine thiolactone. Potent oxygen free radicals such as superoxide anion radical and hydrogen peroxide, are produced during the auto-oxidation of homocysteine. On the other hand, deficiency of folate and vitamin B12 (cobalamin) results in hyperhomocysteinemia since homocysteine converts to methionine by the acquisition of a methyl group from cofactors such as folate in the remethylation process.

Mitochondria are the major site producing oxygen free radicals during the oxidative phosphorylation. Mitochondrial DNA (mtDNA) is easily damaged by oxygen free radicals because of lack of histone backbone and a poor antioxidant mechanism. Thus mtDNA has shorter half-life and higher mutational rate than nuclear DNA. Mutations of mtDNA increase with aging. Cumulative mtDNA damage by oxygen free radicals has been considered to be one of the most probable aging mechanisms. Since aging is a risk factor of the cardiovascular disease, mitochondrial DNA damage with aging may be associated with the development of cardiovascular disease. In previous population-based study, mtDNA content in peripheral blood was inversely correlated with diastolic blood pressure and waist to hip ratio [6].

Recently, it has been shown that in vitro, supra-physiologic concentration of homocysteine decreases mitochondrial gene expression and respiratory rate with evidence suggesting this mediated by generating hydrogen peroxide [7]. However, there is no report showing that a physiologic range of plasma homocysteine concentration affect mtDNA in vivo. In this study, we investigated the relationship between plasma tHcy level and mtDNA content in healthy volunteers. We also investigated the correlation between these two factors and other known cardiovascular risk factors.

Section snippets

Subjects

Sixty healthy women (mean age 40.3 years, range 18–78 years) were recruited from the Ewha Woman's University Sports Center, who visited the spots center for the aerobic exercise training. Their cardiopulmonary function was evaluated by pulmonary function test and exercise electrocardiogram before the study. No subjects had evidence for metabolic disorder, cardiovascular disease, and regular medication. Smokers and ex-smokers were excluded because cigarette smoking could affect the homocysteine

Statistics

All data was presented as mean±SD. Correlations between variables were analyzed using Pearson's correlation. Multiple linear regression was used to determine the independent effect of parameters. Statistical significance was defined as P<0.05.

Anthropometric-biochemical characteristics

Their body mass index, waist to hip ratio, blood pressure, fasting plasma glucose and insulin level, and lipid profiles were shown in Table 2. Average concentration of plasma total homocysteine was 10.0±3.4 μmol/l (mean±SD).

Relationship between plasma total homocysteine concentration and mtDNA content in peripheral blood (Fig. 2)

There was a significant negative correlation between plasma tHcy and mtDNA content in peripheral blood. With raw data, simple correlation analysis gave a Pearson's correlation coefficient of −0.507 (P<0.01), but the scatterplot was skewed hyperbolically (left panel). After

Discussion

In this study, we have demonstrated a negative correlation between plasma total homocysteine (tHcy) level and mitochondrial DNA (mtDNA) content in peripheral blood. We have also shown that plasma tHcy level and mtDNA content are correlated with known atherosclerosis risk factors such as waist to hip ratio, lipid profiles, fasting plasma insulin level, and the HOMA insulin resistance score.

This is consistent with other reports, which have shown that the high level of plasma homocysteine is

Acknowledgements

The authors thank Bong Sun Kang, Jeong Mi Kim and Soo Jin Jeong for a technical assistance. The work was supported by grant from the Korea Ministry of Health and Welfare.

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