Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappaB in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappaB, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappaB. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.

The renin-angiotensin system contributes to atherogenesis. Matrix metalloproteinases (MMP) are thought to participate in plaque destabilization through degradation of extracellular matrix. This study tested whether angiotensin II (ANG II) induces MMP in human vascular smooth muscle cells (SMC). ANG II induced expression of MMP-1, -3, and -9, but not of MMP-2 in SMC. The expression of MMP-1, a key enzyme for collagen degradation, was studied in detail. SMC stimulated with ANG II concentration-dependently released enzymatically active MMP-1. The ANG II type 1 receptor antagonists losartan and candesartan blocked ANG-II-induced MMP-1 release. Inhibition experiments with actinomycin D suggest ANG-II-induced MMP-1 mRNA regulation at the transcriptional level. Decoy oligodeoxynucleotides against nuclear factor-ĸB and activator protein 1 inhibited MMP-1 secretion, demonstrating participation of these transcription factors in MMP-1 transcription. Stimulation of MMP-1 by ANG II depended on cyclooxygenase 2. The antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine, the flavin protein inhibitor diphenylene iodonium, and the NADP(H) oxidase inhibitor apocynin blocked MMP-1 release, suggesting a redox-sensitive mechanism involving NADP(H) oxidase. The reactive oxygen species (ROS) donor 2,3-dimethoxy-1,4-naphthoquinone induced MMP-1 secretion and enhanced ANG-II-stimulated MMP-1 expression. These findings indicate that ROS may increase their own production by activation of NADP(H) oxidase. The capability of ANG II to induce functionally active MMP in human SMC may contribute to the altered plaque composition seen in complicated stages of atherosclerosis.

The diagnostic value of a combination of transoesophageal and transthoracic echocardiography was evaluated in 21 patients with dissection of the aorta. The results were compared with those of computed tomography, aortography, and with findings at operation or necropsy or both. Transthoracic echocardiography identified three of the four patients with type I dissection, two of the five patients with type II dissection, and one of the 12 patients with type III dissection. When transoesophageal echocardiography was used as well the degree of aortic dissection was identified correctly in all 21 patients. In one patient with type I and in eight patients with type III dissection spontaneous echocardiographic contrast with a mural thrombus within the false lumen could be detected. Computed tomography was unable to demonstrate an intimal flap in one of two patients studied with type I dissection, in two of three patients with type II dissection, and in one of nine patients with type III dissection. Aortography was negative in one of two patients studied with type I dissection, two of four patients with type II dissection, and in one of eight patients with type II dissection. The whole thoracic aorta can be imaged by a combination of transthoracic and transoesophageal echocardiography. The addition of transoesophageal echocardiography to transthoracic echocardiography improves the recognition of aortic dissection. Furthermore, this examination can be performed at the bedside and the findings can be used as a basis for treatment.

Experimental data have shown that rIL2 has negative inotropic properties. This has not been investigated in humans with normal left ventricular function. Seventeen consecutive renal cell carcinoma patients who received rIL2 therapy because of dissemination were analyzed before and after treatment with a low dose of rIL2 subcutaneously. Left ventricular ejection Ž . Ž . fraction echocardiography , heart rate variability parameters 24 h electrocardiography , and TNF␣ , IL1␤ and nitric oxide Ž . Ž . metabolites NO were measured. LVEF decreased from 54 " 7 to 50"6% mean " S.D.; P s 0.012 , with a concomitant x Ž . increase in heart rate from 87 " 13 to 94 " 13 beatsrmin Ps 0.031 . All frequency domain HRV parameters decreased: the Ž . Ž . total power from 18.0" 7.9 to 14.0" 5.0 ms Ps 0.001 , the low frequency from 10.3" 5.4 to 8.3" 3.4 ms P s 0.001 , and the Ž . high frequency from 6.3" 2.6 to 4.5" 1.1 ms Ps 0.001 . There was no measurable effect on TNF␣ , IL1␤ concentrations. Ž . Ž . Plasma levels of nitrate NO increased from 22.8" 14.4 to 41.8" 26.6 molrl Ps 0.007 . Conclusions: A low dose of rIL2 x has a negative inotropic effect that may be mediated by increased NO concentrations. It also reduces sympathetic activity as reflected in HRV parameters. ᮊ