Angiotensin II and vascular disease. Studies in rats and atherosclerosis-prone mice

Abstract

Angiotensin II (Ang II) is of importance for a number of physiological processes but also plays an important pathophysiological role in cardiovascular disease. The aim of this thesis was to evaluate the role of Ang II in hypertension-related atherosclerosis and vascular disease and to investigate possible anti-atherosclerotic effects of the angiotensin II, type 2 (AT2) receptor. Interactions with salt intake and with insulin were also investigated. The studies in the current thesis have been performed in rats and genetically modified, atherosclerosis prone mice. The animals have been treated with Ang II, exogenously administered as well as endogenously activated. Animals have also been treated with insulin and/or different dietary manipulations. Interventions in the renin angiotensin system have been performed using antagonists of the angiotensin type 1 (AT1) and AT2 receptors, respectively. We found that both exogenous and endogenous Ang II increased atherosclerosis, however, no evidence for the AT2 receptor to have the suggested anti-atherosclerotic effect. This was true despite an up-regulated AT2 receptor on both mRNA and protein levels and that the major expression site for the AT2 receptor is in the atherosclerotic lesions. The accelerating effect of Ang II on atherosclerosis after endogenous activation is most likely due to its increased blood pressure. High salt diet per se is only mildly atherogenic, however, the combination of Ang II and high salt acts synergistically and increases atherosclerosis to a greater extent compared to Ang II treatment alone. This synergistic effect could be due to an increase in oxidative stress. In the last paper we investigated the in vivo interactions between the renin angiotensin system and insulin in a hyperinsulinemic rat model. This revealed that insulin infusion does not cause hypertension but sensitizes the rats blood pressure to the renin angiotensin system. We found no evidence of sympathoexcitation from insulin and no evidence that hyperinsulinemic rats are hyper-reactive to stressful stimulus. The major conclusions from this thesis are that hyperinsulinemia makes blood pressure control Ang II sensitive. This sensitization may be of importance for vascular damage in diabetes. Ang II accelerates atherosclerosis but the AT2 receptor does not have any anti-atherosclerotic effects. High salt diet does not accelerate atherosclerosis as long as you are able to modulate your renin angiotensin system. However, if the regulation of the renin angiotensin system is defect, for example due to genetics or during stress, high salt diet accelerates atherosclerosis.