RESUMEN
Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSµ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSµ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSµ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.
Asunto(s)
Isquemia/tratamiento farmacológico , Músculo Esquelético/irrigación sanguínea , Distrofia Muscular de Duchenne/tratamiento farmacológico , Nitratos/uso terapéutico , Simpaticolíticos/uso terapéutico , Administración Oral , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Duchenne/metabolismo , Nitratos/administración & dosificación , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Oxígeno/metabolismo , Simpaticolíticos/administración & dosificación , VasoconstricciónRESUMEN
OBJECTIVE: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. RESEARCH DESIGN AND METHODS: Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. RESULTS: Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. CONCLUSION: There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671).
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Haptoglobinas/genética , Lipoproteínas HDL/metabolismo , Vitamina E/uso terapéutico , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Complemento C3/metabolismo , Estudios Cruzados , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatología , Método Doble Ciego , Genotipo , Humanos , Peróxidos Lipídicos/metabolismo , Oxidación-Reducción , Farmacogenética , Receptores de Superficie Celular/biosíntesisRESUMEN
Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.
Asunto(s)
Haptoglobinas/fisiología , Animales , Antioxidantes/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Haptoglobinas/genética , Haptoglobinas/metabolismo , Hemoglobinas/metabolismo , Humanos , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/genética , Enfermedades Vasculares/metabolismoRESUMEN
An emerging paradigm of research has suggested that in the setting of diabetes mellitus (DM) the quality or function of high-density lipoprotein (HDL) may be a determinant of cardiovascular disease risk. Specific structural modifications of HDL protein and lipid components, resulting from oxidative modification, have been proposed to mediate HDL's loss of the ability to promote cholesterol efflux (reverse cholesterol transport), serve as an antioxidant and anti-inflammatory agent. Therefore, inhibiting HDL oxidative modification would be expected to improve its function and provide cardioprotection. Nevertheless, antioxidant strategies to reduce cardiovascular events from atherosclerosis in DM have failed. It has been proposed that this failure may have been due to the inadequate nature of patient selection. High dose antioxidant therapy may only provide benefit to a subset of DM individuals with oxidatively modified HDL. We will review evidence that haptoglobin (Hp) identifies such individuals who can be successfully treated with vitamin E. These data will suggest that a pharmacogenomic approach utilizing the Hp genotype may be useful in identifying individuals who will benefit from antioxidant therapy.