Articles in PresS. Am J Physiol Heart Circ Physiol (December 9, 2005). doi:10.1152/ajpheart.01033.2005 FINAL ACCEPTED VERSION H-01033-2005.R1
满江红朗诵配乐DNA quence variation in the promoter region of the VEGF gene impacts VEGF gene
expression and maximal oxygen consumption.
Steven J. Prior1, James M. Hagberg1, Chad M. Paton1, Larry W. Douglass2, Michael D. Brown1,
John C. McLenithan3, Stephen M. Roth1
1Department of Kinesiology, University of Maryland, College Park, MD
2Department of Animal and Avian Sciences, University of Maryland, College Park, MD
3Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of
Medicine, Baltimore, MD
工程项目管理制度Running head:VEGF haplotype impacts VEGF gene expression and Vo2max
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Address for Correspondence:Steven J. Prior, Ph.D.
Baltimore VA Medical Center
Geriatrics (18), Room 4B-205
10 N. Greene St.
Baltimore, MD 21201
Email: sprior@grecc.umaryland.edu
Phone: 410-605-7000 x4129
Fax: 410-605-7913
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ABSTRACT
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In its role as an endothelial cell proliferation and migration factor, vascular endothelial growth factor (VEGF) can affect peripheral circulation, and therefore impact maximal oxygen consumption (Vo2max). Becau of the role of VEGF, and becau variation in the VEGF gene has the ability to a
lter VEGF gene expression and VEGF protein level, we hypothesized that VEGF gene polymorphisms are related to VEGF gene expression in human myoblasts and Vo2max before and after aerobic exerci training. We analyzed the effects of the VEGF -2578/-1154/-634 promoter region haplotype on VEGF gene expression using a lucifera reporter assay in cultured human myoblasts and found that the AAG and CGC haplotypes resulted in significantly higher hypoxia-stimulated VEGF gene expression than the AGG and CGG haplotypes. Consistent with the results, we found that individuals with at least one copy of the AAG or CGC haplotype had higher Vo2max before and after aerobic exerci training than did subjects with only the AGG and/or CGG haplotype. In conclusion, we found that VEGF -2578/-1154/-634 haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo2max. The results have potential implications for aerobic exerci training and may prove relevant in the study of pathological conditions that can be affected by angiogenesis, such as coronary artery dia and peripheral artery dia.
Key Words: angiogenesis, exerci, genetics, polymorphism
INTRODUCTION
The vasculature of human tissues plays an integral role in survival and function. This role becomes even more prominent in certain pathological conditions (e.g., coronary artery dia (CAD)(33)and peripheral artery dia (PAD)(11)) and physiological conditions (e.g., aerobic exerci(5)) as blood flow to tissues is often limited. This is especially relevant in human skeletal muscle where blood flow, and thus oxygen supply, can limit maximal oxygen consumption (Vo2max)(36). Maximal oxygen consumption (Vo2max) is inverly associated with cardiovascular and all-cau mortality(8), a relationship that has been well documented in a variety of populations. It is also well established that Vo2max is responsive to aerobic exerci training, such that Vo2max typically increas ~15-30% after 3-9 months of training(23, 40). Concordantly, improvement in cardiorespiratory fitness has been shown to result in decread risk of cardiovascular dia mortality and all-cau mortality(8). As the genesis of new vasculature can influence Vo2max by increasing local circulation and oxygen supply, investigation of the mechanisms underlying the process of angiogenesis is of significant clinical interest.
Angiogenesis is a critical phenomenon in the adaptation to aerobic exerci training becau a contributing mechanism to the training-induced increa in Vo2max is an increa in skeletal muscle capillarity(5). This is important becau a proportion of the increa in Vo2max with training is attrib
uted to incread oxygen extraction by the working muscle(35, 40). Angiogenesis can contribute to this increa in oxygen extraction by increasing the capillary surface area for diffusion, decreasing the average O2 diffusion path length in skeletal muscle, and increasing red blood cell transit time through skeletal muscle(31). Increas in arterio-venous oxygen difference (a-vO2D) have been obrved after aerobic exerci training and are responsible, in part, for training-induced increas in Vo2max in older individuals(13, 45, 51).
Aerobic exerci training has been identified as a powerful angiogenic stimulus as studies over the last 3 decades have shown increas in skeletal muscle capillarity up to ~30% in as little as 1-3 months of training(1, 44). Vascular endothelial growth factor (VEGF) has been identified as one of the key regulators of angiogenesis becau it plays a role in endothelial cell proliferation(14) and migration(18). VEGF is expresd in numerous human tissues including skeletal muscle, and recent rearch indicates that VEGF is indeed involved in the angiogenic respon to aerobic exerci(15, 38). For example, aerobic exerci creates a hypoxic condition in skeletal muscle (Po2~2-4 Torr(37, 49)) which upregulates VEGF gene transcription and increas the half-life of VEGF mRNA through hypoxia inducible factor-1 (HIF-1)(27).
Significant variability has been obrved among similar individuals in Vo2max(4), skeletal muscle ca
pillarity(5, 44) and in VEGF gene expression(42). For example, Schultz et al.(42) have demonstrated a range of ~1-fold to 7-fold hypoxic induction of VEGF mRNA expression in monocytes derived from CAD patients. Interestingly, this group found that individuals exhibiting the greatest hypoxic induction of VEGF mRNA expression had greater myocardial collateral circulation development than tho with lower hypoxic induction, indicating functional implications of variable VEGF gene expression(42).
While some proportion of the variability in the aforementioned traits can doubtlessly be attributed to non-genetic factors, there appears to be a significant contribution of genetic factors. Twin studies have revealed significant correlations of Vo2max between sibling pairs(3, 22) and additional rearch has provided heritability estimates for Vo2max and the respon of Vo2max to aerobic exerci training as high as 59% and 47%, respectively; though it is recognized that non-genetic familial influences also contribute to the heritability estimates(2). While the genetic contribution to skeletal muscle capillarity has yet to be defined, investigators have argued that
differences in the vasculature among individuals can be attributed to both environmental factors (e.g. aerobic exerci training), and genetic factors(5, 34). The heritability of VEGF gene expression has not been well studied, but at least two recent reports have demonstrated that polymorphisms within t
he VEGF gene affect VEGF gene expression in specific cell types in vitro(25, 47), indicating a genetic contribution to VEGF gene expression.
DNA quence variation in the promoter region of VEG F gene has previously been associated with differences in VEGF gene and protein expression. The C-2578A(43) (which is linked to an 18bp inrtion/deletion polymorphism at position -2549(6)), G-1154A(43), and G-634C(50) single nucleotide polymorphisms (SNPs) in the promoter region of the VEGF gene have been associated with VEGF protein expression in peripheral blood mononuclear cells, and the VEGF-2578/-1154/-634 haplotype has been associated with VEGF gene expression in cultured GI-1 glioma cells(25), as well as in MCF7 breast cancer cells(47).
Purpo:As the effects of the VEGF promoter region haplotypes have not been investigated in skeletal muscle (a tissue highly relevant for Vo2max), where different factors may regulate VEGF gene expression, the purpo of this project was to investigate the VEGF -2578/-1154/-634promoter region haplotype for effects on VEGF gene expression in cultured skeletal muscle cells, and for association with Vo2max before and after aerobic exerci training.
In addition, the utility of measuring plasma VEGF levels is currently unknown. Plasma VEGF levels
个性游戏名may be indicative of angiogenic activity(21) and may be influenced by acute exerci(16, 24), but the relevance of circulating VEGF protein is not clear. An association has been reported between VEGF-2578/-1154/-634haplotype and plasma VEGF levels in subjects with amyotrophic lateral sclerosis (ALS)(25), but this remains to be obrved in healthy subjects. As it is currently unknown whether plasma VEGF levels are reflective of skeletal muscle VEGF
expression or are predictive of Vo2max, we investigated whether an association exists between plasma VEGF level and VEGF-2578/-1154/-634haplotype, and whether a correlation exists between plasma VEGF level and Vo2max.咸奶茶
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