Insulin-like growth factor induces up-regulation of AT1-receptor gene expression in vascular smooth muscle cells

Abstract

Background Insulin-like growth factor-1 (IGF-1), as well as AT₁-receptor activation, plays a central role in growth processes of cardiac and vascular cells. In order to assess relevant interactions of both systems, the effect of IGF-1 on AT₁-receptor expression was evaluated in vascular smooth muscle cells.

Methods and results Incubation of cultured vascular smooth muscle cells (VSMC) with IGF-1 led to a dose- and time-dependent up-regulation of AT₁-receptor mRNA, as measured by Northern hybridisations. The maximal AT₁-receptor overexpression of 201±70% of control levels was reached after a 24-hour incubation with 100 ng/ml IGF-1. Consequently, AT₁-receptor protein expression was increased to 231±35% of control levels. Experiments under transcriptional blockade showed that AT₁-receptor mRNA stability was not altered by IGF-1, suggesting that transcriptional mechanisms may be involved in IGF-1-induced AT₁-receptor regulation. Preincubation with various pharmacological inhibitors revealed that IGF-1 up-regulated AT₁-receptor expression via activation of p42/44 MAP kinase, whereas tyrosine phosphorylation and PI-3 kinase seemed not to participate in this regulative pathway.

Conclusions IGF-1-induced up-regulation of the AT₁-receptor may be an important interaction by which cellular growth is modulated in the heart as well as in the vasculature. This may have implications for the treatment regimen of patients suffering from hypertension, cardiac hypertrophy, and coronary heart disease.

Keywords

angiotensin II hypertension insulin-like growth factor vascular smooth muscle cells AT1-receptor atherosclerosis

Get full access to this article

View all access options for this article.

References

Caponi AM , Aguilera G. , Fakunding JL , Catt KJ Angiotensin II: receptors and mechanisms of action. In: Biochemical Regulation of Blood Pressure ( Soffer RL , ed.) John Wiley & Sons, New York, 1981; 205-62.

Peach MJ Renin-angiotensin system: biochemistry and mechanism of action. Physiol Rev 1977; 57: 313-70.

Griendling KK , Minieri CA , Ollerenshaw JD , Alexander RW Angiotensin II stimulates NADH and NADPH oxidase activity in cultured smooth muscle cells . Circulation Res 1994; 74: 1141- 8.

Unger T. , Chung O. , Csikos T. et al. Angiotensin receptors. J Hypertens Suppl 1996; 14(5): S95-103.

Griendling KK , Murphy TJ , Alexander RW Molecular biology of the renin-angiotensin system. Circulation 1993; 87: 1816-28.

Nickenig G. , BäumerAT , Grohe C. et al. Estrogen modulates AT1-receptor gene expression in vitro and in vivo. Circulation 1998; 97(22): 2197-201.

Warmholtz A. , Nickenig G. , Schulz E. et al. Increased NADHoxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 1999; 99(15): 2027-33.

Nickenig G. , Jung O. , Strehlow K. et al. Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression. Am J Physiol 1997 ; 272 (Heart Circ Physiol): H2701-H2707 .

Nickenig G. , Sachinidis A. , Michaelsen F. , Böhm M. , Seewald S. , Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation 1997; 95(2): 473-8.

10.

Clemmons DR Exposure to platelet derived growth factor modulates the porcine aortic smooth muscle cell response to somatomedine-C . Endocrinology 1985; 117: 77-83.

11.

Fath A. , Alexander RW , Delafontaine P. Abdominal coarctation increases insulin-like growth factor I mRNA levels in rat aorta. Circulation Res 1992; 72 (2): 271-7.

12.

Ito H. , Hiroe M. , Hirata Y. et al. Insulin-like growth factor I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat myocytes. Circulation 1993; 87: 1715-21.

13.

Bayes-Genis A. , Conover CA , Schwartz RS The insulin-like growth factor axis:A review of atherosclerosis and restenosis. Circulation Res 2000; 86(2): 125-30.

14.

Schiller NK , McNamara DB Balloon catheter vascular injury of the alloxan-induced diabetic rabbit: the role of insulin-like growth factor I. Mol Cell Biochem 1999; 202(1-2): 159-67.

15.

Ververis J. , Ku L. , Delafontaine P. Fibroblast growth factor regulates insulin-like growth factor-binding protein production by vascular smooth muscle cells. Am J Med Sci 1994; 307(2): 77-81.

16.

Dell GC , Morley SD , Mullins JJ , Williams BC , Walker SW Multiple signal transduction systems regulate angiotensin II (AT1) receptor mRNA expression in bovine adrenocortical system. Endocr Res 1996; 22(4): 363-8.

17.

Jones JI , Clemmons DR Insulin-like growth factors and their binding proteins: biological actions . Endocrine Rev 1995; 16(1): 3-34.

18.

Soos MA , Siddle K. Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogenity of insulin-like growth factor I receptors involving hybrids with insulin receptors. Biochem J 1989; 263: 553-63.

19.

Soos MA , Field CE , Siddle K. Purified hybrid insulin/insulin-like growth factor I receptors bind insulin-like growth factor I, but not insulin, with high affinity. Biochem J 1993; 290: 419-26.

20.

Isgaard J. , Tivesten A. , Friberg P. , Bengtsson BA The role of the GH/IGF-I Axis for Cardiac Function and Structure. Horm Metab Res 1999; 31: 50-4.

21.

Chamley JH , Cambell GR , and Ross R. The smooth muscle cell in culture. Physiol Rev 1979; 39: 1-61.

22.

Ross RJ The smooth muscle cell II. growth of smooth muscle cells in culture and formation of elastic fiber. J Cell Biol 1970; 50:172-6.

23.

Murphy TJ , Alexander RW , Griendling KK , Runge MS , and Bernstein KE Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor . Nature 1991; 351: 233-6.

24.

Iyer SN , and Katovich MJ Effect of chronic losartan potassium treatment on fructose induced hypertension . Life Sci 1994; 55: 139-44.

25.

Pitt B. The potential use of angiotensin-converting enzyme inhibitors in patients with hyperlipidemia. Am J Cardiol 1997; 79(5A): 24-8.

26.

Berkenboom G. , Langer I. , CarpentierY , Grosfils K. , Fontaine J. Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins.A bradykinin-dependent mechanism . Hypertension 1997; 30(1): 371-6.

27.

Lievre M. , Gueret P. , Gayet C. et al. on behalf of the HYCAR Study Group . Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. Hypertension 1995; 25: 92-7.

28.

Svedberg K. , Kjekhurst J. , Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril. Eur Heart J 1999; 20:136-9.

29.

Yusuf S. , Sleight P. , Pogue J. , Bosch J. , Davies R. , Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Study Investigators . N Engl J Med 2000; 342(3): 145-53.

30.

Nickenig G. , Röling J. , Strehlow K. , Schnabel P. , Böhm M. Insulin induces upregulation of vascular AT1-receptor gene expression by posttranscriptional mechanisms . Circulation 1998; 98: 2453-60.

31.

Nickenig G. and Murphy TJ Down-regulation by growth factors of vascular smooth muscle angiotensin receptor gene expression. Mol Pharm 1994; 46: 653-9.