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Objective: The present study was designed to determine the effects of insulin on cytosolic angiotensin II production and proliferation in cultured rat vascular smooth muscle cells., Design and Methods: Vascular smooth muscle cells were incubated with insulin for 48 h. Cytosolic angiotensin I and II were determined by radioimmunoassays of purified cell homogenates. Angiotensin II was also detected by immunohistochemistry of intact cells. Cell proliferation was determined by pulse labeling with radiolabeled thymidine. Angiotensinogen mRNA expression was determined by slot-blot analysis., Results: Insulin significantly increased cytosolic angiotensin II concentration in vascular smooth muscle cells. Lisinopril, omapatrilat and irbesartan inhibited this increase of angiotensin II, but had no effect on angiotensin I levels. Immunohistochemical staining confirmed the presence of angiotensin II in control and insulin-treated vascular smooth muscle cells. Insulin increased cell proliferation, and addition of lisinopril, omapatrilat or irbesartan inhibited this effect. Insulin also increased expression of angiotensinogen mRNA in cultured vascular smooth muscle cells, but PD98059, a mitogen-activated protein kinase inhibitor, prevented the rise in angiotensinogen expression., Conclusion: These results support the concept that insulin stimulates angiotensin II production in cultured vascular smooth muscle cells through a mitogen-activated, protein kinase-dependent pathway that might be a factor in the progression of atherosclerosis. Agents that block the renin-angiotensin system have direct protective effects, reducing vascular angiotensin II and growth of vascular smooth muscle cells and are thus of cardiovascular benefit.

Background: Fish oil has been shown to improve blood pressure (BP) in some disease states by an unknown mechanism. We tested the ability of fish oil to prevent vascular dysfunction in fructose-fed rats, a model of insulin resistance and hypertension. Methods: Rats were placed on three diets: 1) regular rat diet (control); 2) diet containing 60% fructose (FFR); or 3) diet containing 60% fructose and 4.4% fish oil (FFR+FO). After 8 weeks, blood, heart, aorta, and mesenteric artery tissue were collected from each animal. Secondary branch segments of mesenteric arteries were isolated for vascular reactivity studies. Results: Systolic BP increased significantly in the FFR but was reduced to control levels by the addition of fish oil to the diet. In the mesenteric artery segments from FFR, the dose-response curves to acetylcholine were significantly shifted to the right compared with those of control rats and rats on the fish oil diet. Expression of endothelial nitric oxide synthase (eNOS) protein and mRNA was reduced in the FFR aortas and hearts, and this reduction was reversed by the fish oil. Dietary fish oil prevented the hyperlipidemia that occurred in the FFR but did not prevent hyperinsulinemia. Plasma concentrations of hydrogen peroxide, 8-isoprostane, and monocyte chemoattractant protein-1 were significantly elevated in the FFR and were significantly lower in the FFR treated with fish oil. Conclusions: These results demonstrate that dietary fish oil prevents vascular dysfunction in FFR and that this effect of fish oil is associated with increased eNOS expression and decreased oxidative stress. [Copyright &y& Elsevier]