Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase

Abstract

eleterious left ventricular (LV) remodeling after myocardial infarction (MI) is the major cause of heart failure. Although therapeutic strategies designed to limit ventricular remodeling after MI can decrease the incidence of congestive heart failure and improve survival, 1 mechanisms of remodeling process remain not fully elucidated. At the cellular level, reactive oxygen species (ROS) and oxidative stress play a key role in regulating myocardial remodeling. 2,3 In the stressed heart, there is an increase in the production of superoxide from multiple sources such as mitochondria, 4 NADPH oxidase, 5 xanthine oxidase, 6 and nitric oxide (NO) synthase. 7,8 NO is a diffusible highly reactive gas formed by 3 NO synthase (NOS) isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The eNOS-derived NO serves to promote vascular homeostasis and might affect cardiac myocyte function. 9 However, NOS itself can generate superoxide under certain pathological conditions. 10 We have reported that transgenic overexpression of eNOS in apolipoprotein E knockout mice paradoxically increased vascular superoxide production because of enzymatic uncoupling of eNOS. 11 These findings could be explained by relative deficiency of the reducing cofactor of eNOS, tetrahydrobiopterin (BH4). BH4 plays a crucial role in facilitating electron transfer from eNOS reductase domain, maintaining the heme prosthetic group in its redox active form, and promoting formation of active NOS homodimer. Therefore, a relative lack of BH4 results in increased superoxide production by promoting eNOS uncoupling. 12,13 NO from eNOS was shown to protect the heart from various stimuli. Previous studies have shown that cardiac remodeling after MI was attenuated in transgenic mice overexpressing eNOS, 14,15 but deteriorated in mice deficient of the eNOS gene (eNOS KO mice). 16 Similarly, pressure overload-induced LV remodeling was exacerbated in eNOS KO mice. 17,18 Takimoto et al investigated the role of eNOS in the LV remodeling induced by transverse aortic constric- Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and ResultsRats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the n...

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

“…BH 4 is highly sensitive to oxidation and, with BH 4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS into a superoxide-producing enzyme. 40 In our ex vivo experiments on vessels from patients with HD, exposure to exogenous BH 4 or to resveratrol restored eNOS functionality and, hence, reduced oxidative stress.…”

“…BH 4 is highly sensitive to oxidation and, with BH 4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS into a superoxide-producing enzyme. 40 In our ex vivo experiments on vessels from patients with HD, exposure to exogenous BH 4 or to resveratrol restored eNOS functionality and, hence, reduced oxidative stress.The action we observed on NO occurs through an AMPKdependent mechanism. It was recently proposed that misregulation of AMPK is involved in the metabolic defects underlying progression to dysmetabolic syndrome.…”

Controlled Release of Matrix Metalloproteinase-1 Plasmid DNA Prevents Left Ventricular Remodeling in Chronic Myocardial Infarction of Rats

“…[23][24][25][26] Although the increase in reparative fibrosis and ECM serves to preserve the structural integrity of infarcted tissue in the early phase of MI, in the chronic phase, the accumulation of a large amount of fibrosis, especially interstitial fibrosis, leads to ventricular diastolic dysfunction rather than preservation of cardiac structure. [27][28][29][30] In our rat model of MI, heart function continued to deteriorate 4-8 weeks after MI in the MI group, while the injection of MMP-1 plasmid DNA significantly improved heart function.…”

Beneficial Effects of Growth Hormone-Releasing Peptide on Myocardial Oxidative Stress and Left Ventricular Dysfunction in Dilated Cardiomyopathic Hamsters

“…[24][25][26] Our recent studies have shown that myocardial oxidative stress is enhanced in the initial development of LV dysfunction in TO-2 hamsters. [12][13][14] In the present study, we demonstrated that the GSH/GSSG ratio was decreased in the failing heart of untreated TO-2 hamsters compared with F1B control hamsters at 12 weeks of age.…”