Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia

Abstract

Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine Ͼ15 mol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to L-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n ϭ 50) and HHcy (n ϭ 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 Ϯ 32.23 vs. 119.50 Ϯ 37.68 mol/l and 1.43 Ϯ 0.46 vs. 1.73 Ϯ 0.56 pmol/ml, all P Ͻ 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 Ϯ 0.49 vs. 3.09 Ϯ 0.52, P Ͻ 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part. nitric oxide HYPERHOMOCYSTEINEMIA (HHcy) is an independent risk factor for coronary artery disease (CAD) (2). The possible mechanism of accelerated vascular disease in HHcy includes endothelial cell damage, vascular endothelial dysfunction, and enhanced oxidative stress (4, 17). Increasing evidence suggests that HHcy may adversely affect CAD by decreasing vascular endothelial function. In healthy individuals, homocysteine (Hcy) has been associated with impaired coronary microvascular dilator function (16). In models of acute methionineinduced HHcy, endothelium-dependent dilation was significantly inhibited in parallel with elevated plasma Hcy levels (1). HHcy induces NADPH oxidase activity, thus contributing to increased reactive oxygen species (ROS) production in rat coronary vessels (19).Nitric oxide (NO) protects against CAD through anti-inflammatory and antioxidant effects. Loss of NO bioavailability is a key feature of endothelial dysfunction preceding the appearance of atherosclerosis. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthase (NOS). When BH4 levels are inadequate, endothelial NOS (eNOS) is no longer coupled to L-arginine oxidation, which results in ROS rather than NO production, thereby inducing vascular endothelial dysfunction (15). Administration of BH4 improves endothelial function in diabetic patients and patients with or without CAD (9 -1...

Reply to letter to the editor: coronary flow velocity reserve was impaired in chronic hyperhomocysteinemic patients: why?

“…Coronary flow velocity reserve (CFVR), which is derived from the ratio of maximal hyperemic to basal coronary blood flow, is an accepted index for assessment of the coronary microcirculation and provides important information about coronary endothelial function. We thank Dr. Kietadisorn et al (10a) for their interest in our paper (9). We fully agree that CFVR as an independent index of coronary microvascular function has multiple limitations.…”

Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

“…Reduced CFVR is an early prognostic indicator of coronary atherosclerotic heart disease (28). Our previous studies also demonstrated a positive association between CFVR and endothelial function in patients either with type 2 diabetes-associated coronary artery disease or with hyperhomocysteinemia (18,27,39).…”

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

“…In addition, statin therapy did not restore endothelial function to normal. The reason for this effect remains unknown; however, plasma homocysteine remained elevated throughout the statin treatment and hyperhomocysteinemia is well documented to cause endothelial dysfunction via separate mechanisms, including increased oxidative stress 21) and reduction in eNOS co-factors 22) . It remains unclear whether the roles of statins in the prevention of CVD are solely related to its lipidAlfon and colleagues showed reduced TC by simvastatin treatment in rabbits fed 0.5% cholesterol ＋15% coconut oil for 10 weeks 15) .…”