[Frontiers in Bioscience S3, 655-661, January 1, 2011]

Regulation of protein expression by L-arginine in endothelial cells

Xiaoqing Lei1, Cuiping Feng2, Chuang Liu1, Guoyao Wu1,3,4, Cynthia J. Meininger4, Fenglai Wang1, Defa Li1, Junjun Wang1,3

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China 100193, 2Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China 100029, 3Department of Animal Science and Faculty of Nutrition, Texas A&M University, College Station, TX, 77843, 4Cardiovascular Research Institute, Texas A and M Health Science Center, Temple, TX, 76504


1. Abstract
2. Introduction
3. Comparative proteome analysis of endothelial cells exposed to arginine
4. Conclusion and perspectives
5. Acknowledgements
6. References


L-Arginine is a conditionally essential amino acid for humans and plays an important role in the regulation of cardiovascular function and antioxidative defense. Previous studies have focused on the important role of L-arginine as a physiological precursor in the generation of nitric oxide and polyamines in endothelial cells (cells that line the interior surface of blood vessels). Because of the rapid development of high-throughput proteomics technology, there is now growing interest in studying roles for L-arginine in modulating endothelial-cell protein expression. Of particular interest, recent proteomics analysis has shown that treatment of coronary venular endothelial cells with a physiological level of L-arginine (e.g., 0.1 mM) increases expression of structural proteins (vimentin and tropomyosin) and cytochrome bc1 complex iii-chain A, while decreasing expression of stress-related proteins (PDZ domain containing-3), in these cells. These findings aid in elucidating the mechanisms responsible for the beneficial effect of physiological levels of L-arginine on the circulatory system.


Most mammals (including humans, pigs, sheep, and rats) can synthesize L-arginine from glutamine, glutamate, and proline via pyrroline-5-carboxylate as an essential intermediate (1). However, compelling evidence shows that L-arginine is a conditionally essential amino acid for humans and pigs, depending on developmental stages and disease states (1). This nutrient serves as the nitrogenous precursor for synthesis of nitric oxide (NO; a major vasodilator), polyamines (key regulators of DNA and protein synthesis), proline (a major constituent of extracellular matrix protein), creatine (an antioxidant and a crucial element of energy metabolism in muscle and the central nervous system), and proteins (2-4). L-Arginine plays an important role in the regulation of angiogenesis (growth of new vessels from the existing ones) and cardiovascular function (5). This beneficial effect of arginine holds great promise in enhancing wound healing, improving microcirculatory function, promoting maternal and fetal development, and treating various vascular disorders (including hypertension and atherosclerosis) (6-10).

Physiological levels of NO have potent antioxidant and anti-atherosclerotic actions (5). Previous biochemical studies have focused on the role of L-arginine in the generation of NO and polyamines (11, 12), as well as oxidative defense (13) in endothelial cells. Available evidence shows that increasing extracellular levels of arginine drives endothelial production of NO (14), which then relaxes smooth muscle cells and stimulates blood flow. In humans and experimental animal models, an increase in blood flow causes fluid shear stress, which is a major determinant of arterial tone and vascular remodeling (5, 15). Thus, it is possible that arginine coordinately modulates both metabolic pathways and structure in the vascular system through alterations in protein profiles. However, at present, little is known about the physiological effect of arginine on changes in the proteome of endothelial cells.

The rapid development of high-throughput proteomics technologies in recent years has facilitated the simultaneous analysis of thousands of proteins in cells or tissues, therefore providing a useful tool for discovery research in cardiovascular research (5, 16-19). The major objective of this article is to highlight recent advances in effects of L-arginine on the proteome of endothelial cells. The new knowledge will help define the molecular and cellular mechanisms whereby L-arginine exerts beneficial effects on the circulatory system.


Coronary venular endothelial cells (CVEC) have been used to study mechanisms that regulate angiogenesis (20). A representative of the proteome in these cells, which is based on the 2-dimentional polyacrylamide gel electrophoresis (2D-PAGE) technique and matrix-assisted laser desorption ionization (MALDI) mass spectrometry, is shown in Figure 1. Addition of 0.1 mM L-arginine (a physiological level of arginine in human plasma) to culture medium containing 0.015 mM L-arginine differentially affects the levels of nine protein spots in 2D gels (Figure 1). Note that an arginine concentration of 0.015 mM was present in plasma of neonates or adults with vascular dysfunction (21) and is generally considered to be deficient for mammals (22, 23).

Biochemical properties of the proteins which exhibited changes in response to arginine treatment are summarized in Table 1. Interestingly, vimentin and tropomyosin are up-regulated in response to treatment with 0.1 mM L-arginine, whereas the opposite result is obtained for PDZ domain-containing protein-3. Furthermore, concentrations of cytochrome bc1 complex 3-chain A are increased in cells cultured containing 0.1 mM L-arginine, in comparison with cell cultures with 0.015 mM L-arginine (Figure 1). It is necessary that results of proteomic analysis be verified using both quantitative RT-PCR and western blot. This can be achieved by randomly selecting one or more of the differentially expressed proteins. The example shown is mRNA and protein levels for vimentin in CVEC treated with 0.015 or 0.1 mM L-arginine (Figure 2).

Although much attention has been focused on arginine metabolism and the regulatory role of NO in cell metabolism (17, 24, 25), little is known about the effect of this amino acid on expression of proteins in vascular endothelial cells. Thus, the finding that physiological levels of arginine affect the abundance of four proteins that are related to cell structure and modulation of oxidative response is novel and important. In particular, concentrations of 2 structural proteins (vimentin and tropomyosin) and cytochrome bc1 complex iii- chain A related to oxidative phosphorylation are increased but the concentration of a signaling protein (PDZ domain containing-protein 3) is decreased in CVEC cultured with 0.1 mM L-arginine. These results provide the first description of changes in the proteome of endothelial cells in response to supplementation of arginine to an arginine-deficient medium and also help elucidate the mechanisms for the beneficial effect of arginine on improving cardiovascular function.

Vimentin is a member of the intermediate filament family of proteins, which plays an important structural role in eukaryotic cells (26). These proteins, along with actin microfilaments and microtubules, constitute the cytoskeleton. Vimentin is expressed abundantly in mesenchyme-derived cells, including endothelial and vascular smooth muscle cells, where this filament primarily functions as an intracellular scaffold to support cell strength and tissue integrity (27). There is evidence that vimentin regulates the migration and proliferation of endothelial cells (28, 29). In addition, vimentin plays a key role in the modulation of vascular tone, possibly by modulating NO synthesis in endothelial cells (30). However, the underlying mechanism is unknown. It is possible that vimentin interacts with caveolin-bound eNOS on the plasma membrane, thereby affecting eNOS phosphorylation and activity. In support of this view, vimentin is readily phosphorylated by different protein kinases (31). Interestingly, six protein spots corresponding to vimentin were differentially expressed in CVEC in response to a physiological concentration of arginine (Table 1 and Figure 1). Also, mRNA levels for vimentin were enhanced in arginine-treated cells (Figure 2). Therefore, we suggest that physiological levels of arginine are necessary for optimal expression of the vimentin gene and protein in endothelial cells. This may be associated with augmented production of NO (an angiogenic factor (32)) and enhanced CVEC proliferation (11).

Tropomyosin is another structural protein whose levels were increased in CVEC in response to supplementation of arginine to an arginine-deficient medium. Tropomyosin is a major microfilament-associated and actin-binding protein in endothelial cells (33). This protein is crucial for maintaining hemodynamic shear stress responses and thus for regulating vessel wall function (34). Interestingly, the synthesis of tropomyosin is stimulated at the post-transcriptional level in proliferating endothelial cells (33). Conversely, reduced concentration of tropomyosin is associated with impaired angiogenesis in blood vessels (35). These results indicate an important role for arginine in regulating the synthesis of cytoskeleton-associated proteins in endothelial cells, as recently reported for global proteins in skeletal muscle cells (36, 37) and mammary gland (38).

L-Arginine is known to improve mitochondrial function in many cell types (39). Interestingly, supplementing arginine to an arginine-deficient culture medium enhances the abundance of cytochrome bc1 in CVEC (Table 1). Cytochrome bc1 (also known as ubiquinol:ferricytochrome c oxidoreductase) resides in the inner mitochondrial membrane and is the complex III of the respiratory chain (40). This complex transfers electrons from ubihydroquinone to cytochrome c, generating a proton gradient across the mitochondrial membrane and, therefore, the oxidation of substrates to yield water. When cytochrome bc1 activity is reduced, superoxide anion (O2-) production is enhanced, resulting in oxidative stress in cells (41). Conversely, when expression of the cytochrome bc1 protein complex is stimulated in response to L-arginine, the generation of superoxide anion and related other reactive oxygen species (e.g., H2O2 and peroxides) is reduced (23). This outcome would minimize cellular concentrations of oxidants. Thus, our new observation offers an explanation for the previous finding that arginine plays a critical role in preventing oxidative stress in cultured endothelial cells (13). Additionally, in response to an improved redox state, expression of key antioxidant proteins is generally attenuated (22, 42). In support of this view, supplementing arginine to culture medium reduces the concentrations of stress-related proteins (PDZ domain containing-protein 3) (43) in CVEC.


In conclusion, proteomic analysis reveals for the first time that a physiological level of arginine alters expression of key proteins related to microfilament function and oxidative defense in CVEC. The changes in these structural and regulatory proteins are associated with improvement of the cellular redox state and enhanced NO production in endothelial cells. These novel findings aid in elucidating the mechanisms responsible for the beneficial action of arginine on the endothelium. At present, it is not known whether L-arginine directly or indirectly regulates protein expression in endothelial cells. We must also recognize that the chemical structure of L-arginine is unique in that it contains a guanidino group and is a basic substance at intracellular physiological pH. We do not rule out a possibility that L-arginine modulates gene expression through one of its metabolites. Thus, we present Figure 3 to propose a mechanism whereby L-arginine increases the expression of vimentin, tropomysin, and cytochrome bc1 in endothelial cells. According to this model, both L-arginine and NO may activate mammalian target of rapamycin (mTOR, a protein kinase) by stimulating its phosphorylation (37,54). Polyamines (products of arginine catabolism via arginase) enhance the transcription of specific genes to form respective mRNAs (21). The translation of mRNAs into proteins requires both polyamines and mTOR for initiating the formation of polypeptides (55-58), including vimentin, tropomysin, and cytochrome bc1. Additionally, mTOR and NO may inhibit degradation of these proteins by proteases and peptidases (59,60). Such changes in the synthesis and degradation of vimentin, tropomysin, and cytochrome bc1 could lead to an increase in their abundance in endothelial cells. Future studies are warranted to test these novel and important hypotheses.


Xiaoqing Lei and Cuiping Feng equally contributed to this work. The authors' research was supported by the National Natural Science Foundation of China (u0731001, 30810103902, 30871808 and 30971256), Beijing Natural Science Foundation (6082017), American Heart Association-TX (0755024Y and 10GRNT4480020), Texas AgriLife Research (No. H-8200), and the Thousand-People-Talent program at China Agricultural University.


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Abbreviations: CVEC: coronary venular endothelial cells; DMEM: Dulbecco's modified Eagle's medium; 2D-PAGE: 2-dimentional polyacrylamide gel electrophoresis; DPBS: Dulbecco's phosphate-buffered saline; FBS: fetal bovine serum; MALDI: matrix-assisted laser desorption ionization; NO: nitric oxide; NOS: nitric oxide synthase; PBST: PBS with 0.2% Tween 20; PCR: polymerase chair reaction; PMF: peptide mass fingerprinting; RT-PCR: real-time polymerase chair reaction.

Key Words Arginine, Endothelial Cells, Proteomics, Vimentin, Review

Send correspondence to: Junjun Wang, State Key Laboratory of Animal Nutrition, China Agricultural University, No. 2. Yuanmingyuan West Road, Beijing, China, 100193, Tel: 86-10-62733588, Fax: 86-10-62733688, E-mail:jkywjj@hotmail.com