Abstract
Retinol-binding protein 4 (RBP4) is a newly discovered adipocytokine related to insulin resistance (IR). Hyperinsulinemia and IR are the major risk factors for cardiovascular diseases (CVD). The role of RBP4 in CVD has not yet been determined. The present study was designed to analyze the correlation of RBP4 and CVD risk factors and to evaluate the role of RBP4 in proliferation of vascular smooth muscle cells during hyperinsulinemia and the underlying mechanisms. Plasma RBP4 concentration, IR-related indexes, and cardiovascular risk factors were measured from blood samples of hyperinsulinemic rats (HIns) and control SD rats (Cons). The vascular morphology and the expression of ERK1/2, p-ERK1/2 in arterial tissues of rats were assessed. Different concentrations of RBP4 (1, 4 μg/ml) were used as intervention factor during insulin-induced aortic smooth muscle cells (RASMCs) proliferation. The expression of cell growth signaling pathways was assessed to identify the active pathway during this proliferation. Specifically, ERK1/2 inhibitor PD98059 and JAK2 inhibitor AG490 were used to detect it. RBP4 expression was higher in HIns compared with Cons (p < 0.01). Plasma RBP4 concentrations were positively correlated with TG (r = 0.490), hsCRP (r = 0.565), media thickness (r = 0.890), and p-ERK1/2 protein (r = 0.746) (p < 0.05 each). In cultured RASMCs, RBP4 enhanced insulin-induced proliferation of cells and expression of p-ERK1/2 and p-JAK2. Blockade of ERK1/2 signaling pathway inhibited RBP4-induced proliferation of RASMCs, while suppressing JAK2 remains unchanged. These results suggest that plasma RBP4 concentrations were associated with CVD. In addition, RBP4 increases the proliferation of VSMCs induced by hyperinsulinism via activation of MAPK signaling pathway.
Similar content being viewed by others
References
R.N. Al-Harithy, S. Al-Ghamdi, Serum resistin, adiposity and insulin resistance in Saudi women with type 2 diabetes mellitus. Ann. Saudi Med. 25, 283–287 (2005)
I.B. Bauche, S.A. El Mkadem, R. Rezsohazy, T. Funahashi, N. Maeda et al., Adiponectin downregulates its own production and the expression of its AdipoR2 receptor in transgenic mice. Biochem. Biophys. Res. Commun. 345, 1414–1424 (2006)
Q. Yang, T.E. Graham, N. Mody, F. Preitner, O.D. Peroni et al., Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005)
Y.M. Cho, B.S. Youn, H. Lee, N. Lee, S.S. Min et al., Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care 29, 2457–2461 (2006)
T.E. Graham, Q. Yang, M. Bluher, A. Hammarstedt, T.P. Ciaraldi et al., Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N. Engl. J. Med. 354, 2552–2563 (2006)
N. Kloeting, T.E. Graham, J. Berndt, S. Kralisch, P. Kovacs et al., Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 6, 79–87 (2007)
R. Ribel-Madsen, M. Friedrichsen, A. Vaag, P. Poulsen, Retinol-binding protein 4 in twins regulatory mechanisms and impact of circulating and tissue expression levels on insulin secretion and action. Diabetes 58, 54–60 (2009)
N. Stefan, F. Schick, A.M. Hennige, E. Schleicher, H. Staiger et al., High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans. Diabetes Care 30, 1173–1178 (2007)
K. Takebayashi, M. Suetsugu, S. Wakabayashi, Y. Aso, T. Inukai, Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J. Clin. Endocrinol. Metab. 92, 2712–2719 (2007)
J.P. Despres, B. Lamarche, P. Mauriege, B. Cantin, G.R. Dagenais et al., Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl. J. Med. 334, 952–957 (1996)
C. Giannattasio, G. Mancia, Arterial distensibility in humans. Modulating mechanisms, alterations in diseases and effects of treatment. J. Hypertens. 20, 1889–1899 (2002)
C. Page, A.F. Doubell, Mitogen-activated protein kinase (MAPK) in cardiac tissues. Mol. Cell. Biochem. 157, 49–57 (1996)
J.E. Pessin, A.R. Saltiel, Signaling pathways in insulin action: molecular targets of insulin resistance. J. Clin. Investig. 106, 165–169 (2000)
K. Cusi, K. Maezono, A. Osman, M. Pendergrass, M.E. Patti et al., Insulin resistance differentially affects the PI3-kinase- and MAP kinase-mediated signaling in human muscle. J. Clin. Investig. 105, 311–320 (2000)
Z. Mallat, T. Simon, J. Benessiano, K. Clement, S. Taleb et al., Retinol-binding protein 4 and prediction of incident coronary events in healthy men and women. J. Clin. Endocrinol. Metab. 94, 255–260 (2008)
M.J. Mahmoudi, M. Mahmoudi, F. Siassi, M. Hedayat, P. Pasalar et al., Circulating retinol-binding protein 4 concentrations in patients with coronary artery disease and patients with type 2 diabetes mellitus. Int. J. Diabetes Dev. Ctries. 32, 105–110 (2012)
T. Bobbert, J. Raila, F. Schwarz, K. Mai, A. Henze et al., Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. Atherosclerosis 213, 549–551 (2010)
E. Ingelsson, L. Lind, Circulating retinol-binding protein 4 and subclinical cardiovascular disease in the elderly. Diabetes Care 32, 733–735 (2009)
M. von Eynatten, P.M. Lepper, D. Liu, K. Lang, M. Baumann et al., Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease. Diabetologia 50, 1930–1937 (2007)
J. Wu, Y.-H. Shi, D.-M. Niu, H.-Q. Li, C.-N. Zhang et al., Association among retinol-binding protein 4, small dense LDL cholesterol and oxidized LDL levels in dyslipidemia subjects. Clin. Biochem. 45, 619–622 (2012)
E. Ingelsson, J. Sundström, H. Melhus, K. Michaëlsson, C. Berne et al., Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly. Atherosclerosis 206, 239–244 (2009)
A. Cabré, I. Lázaro, J. Girona, J. Manzanares, F. Marimón et al., Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes. J. Intern. Med. 262, 496–503 (2007)
L. Poretsky, B. Glover, V. Laumas, M. Kalin, A. Dunaif, The effects of experimental hyperinsulinemia on steroid secretion, ovarian 125I insulin binding, and ovarian 125I insulin-like growth-factor I binding in the rat. Endocrinology 122, 581–585 (1988)
J. Radziuk, Insulin sensitivity and its measurement: structural commonalities among the methods. J. Clin. Endocrinol. Metab. 85, 4426–4433 (2000)
C.C.L. Wang, I. Gurevich, B. Draznin, Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways. Diabetes 52, 2562–2569 (2003)
C–.C. Lin, M–.M. Lai, T.-C. Li, C.-I. Li, C.-S. Liu et al., Relationship between serum retinol-binding protein 4 and visfatin and the metabolic syndrome. Diabetes Res. Clin. Pract. 85, 24–29 (2009)
Q. Qi, Z. Yu, X. Ye, F. Zhao, P. Huang et al., Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people. J. Clin. Endocrinol. Metab. 92, 4827–4834 (2007)
B. Verges, B. Guiu, J.P. Cercueil, L. Duvillard, I. Robin et al., Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 32, 3050–3057 (2012)
S. Usui, M. Ichimura, S. Ikeda, M. Okamoto, Association between serum retinol-binding protein 4 and small dense low-density lipoprotein cholesterol levels in young adult women. Clin. Chim. Acta 399, 45–48 (2009)
N. Mostafaie, C. Sebesta, S. Zehetmayer, S. Jungwirth, K.R. Huber et al., Circulating retinol-binding protein 4 and metabolic syndrome in the elderly. Wien. Med. Wochenschr. 161, 505–510 (2011)
A. Yoshida, Y. Matsutani, Y. Fukuchi, K. Saito, M. Naito, Analysis of the factors contributing to serum retinol binding protein and transthyretin levels in Japanese adults. J. Atheroscler. Thromb. 13, 209–215 (2006)
W. Jia, H. Wu, Y. Bao, C. Wang, J. Lu et al., Association of serum retinol-binding protein 4 and visceral adiposity in chinese subjects with and without type 2 diabetes. J. Clin. Endocrinol. Metab. 92, 3224–3229 (2007)
N. Vu-Dac, P. Gervois, I.P. Torra, J.C. Fruchart, V. Kosykh et al., Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids. J. Clin. Investig. 102, 625–632 (1998)
G. Assmann, H. Schulte, A. von Eckardstein, Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am. J. Cardiol. 77, 1179–1184 (1996)
M.J. Stampfer, R.M. Krauss, J. Ma, P.J. Blanche, L.G. Holl et al., A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA, J. Am. Med. Assoc. 276, 882–888 (1996)
P. Libby, Inflammation in atherosclerosis. Nature 420, 868–874 (2002)
N. Rifai, P.M. Ridker, High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin. Chem. 47, 403–411 (2001)
S. Watanabe, W. Mu, A. Kahn, N. Jing, J.H. Li et al., Role of JAK/STAT pathway in IL-6-induced activation of vascular smooth muscle cells. Am. J. Nephrol. 24, 387–392 (2004)
I. Neeli, Z.M. Liu, N. Dronadula, Z.A. Ma, G.N. Rao, An essential role of the Jak-2/STAT-3/cytosolic phospholipase A(2) axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility. J. Biol. Chem. 279, 46122–46128 (2004)
S. Sahar, R.S. Dwarakanath, M.A. Reddy, L. Lanting, I. Todorov et al., Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells—a novel cross-talk in the pathogenesis of atherosclerosis. Circ. Res. 96, 1064–1071 (2005)
K. Takebayashi, R. Sohma, Y. Aso, T. Inukai, Effects of retinol binding protein-4 on vascular endothelial cells. Biochem. Biophys. Res. Commun. 408, 58–64 (2011)
N. Takashima, H. Tomoike, N. Iwai, Retinol-binding protein 4 and insulin resistance. N Engl. J. Med. 355, 1392 (2006); author reply 1394–1395
S.K. Frey, J. Spranger, A. Henze, A.F. Pfeiffer, F.J. Schweigert et al., Factors that influence retinol-binding protein 4-transthyretin interaction are not altered in overweight subjects and overweight subjects with type 2 diabetes mellitus. Metab. Clin. Exp. 58, 1386–1392 (2009)
A. Ost, A. Danielsson, M. Liden, U. Eriksson, F.H. Nystrom et al., Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB J. 21, 3696–3704 (2007)
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Li, F., Xia, K., Sheikh, M.S.A. et al. Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation. Endocrine 48, 472–482 (2015). https://doi.org/10.1007/s12020-014-0304-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0304-0