INSULIN-MEDIATED GROWTH IN AORTIC SMOOTH-MUSCLE AND THE VASCULAR RENIN-ANGIOTENSIN SYSTEM

Insulin has been shown to directly affect blood vessel tone and to pro mote vascular hypertrophy, but the mechanism of these actions remains uncertain. Because angiotensin I (Ang I)-converting enzyme inhibitors have been shown to improve insulin action and to impede the progressio n of vascular hypertrophy in hypertensive animal models, it is possibl e that the vascular properties of insulin may be mediated through the tissue renin-angiotensin system (RAS), To evaluate this relationship, we first investigated the effect of insulin on components of the RAS u sing cultured rat vascular smooth muscle cells (VSMCs). Insulin treatm ent (1000 mu U/mL) markedly increased angiotensinogen mRNA expression and angiotensinogen production. We next investigated the role of the R AS in insulin-mediated cell proliferation, using [H-3]thymidine uptake . Studies were done both with insulin alone and in the presence of cap topril (1 X 10(-5) to 10(-5) mol/L) and losartan (1 x 10(-9) to 10(-7) mol/L). [H-3]Thymidine uptake was increased significantly by 1000 mu U/mL insulin, and this stimulation was reduced by 1 x 10(-6) mol/L cap topril (-38.8%. P<0.05) and by 1 X 10(-8) mol/L losartan (-37.5%, P<0. 05). Further studies showed that the degree of insulin-mediated [H-3]t hymidine uptake in VSMCs could be duplicated by 4 X 10(-10) mol/L Ang II. Losartan reduced the effects of both Ang II and insulin on [H-3]th ymidine uptake by about 40% to 45% of baseline (P<0.05). Captopril red uced insulin-mediated [H-3]-thymidine uptake but did not affect Ang II -mediated [H-3]thymidine uptake. In summary, insulin induced significa nt stimulation of angiotensinogen expression and production and stimul ated growth similar to that seen with Ang II in cultured rat VSMCs, In hibition of Ang II production or its binding to the Ang IT type 1 (AT( 1)) receptor inhibited insulin-mediated growth in a fashion similar to that seen with inhibition of Ang II-mediated growth. Thus, insulin ca n modulate the vascular RAS, and the effect of insulin on vascular gro wth may be via direct effects on angiotensinogen expression and transl ation operative through both the AT(1) receptor and the conversion of Ang I to Ang II.