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Central role of the AT(1)-receptor in atherosclerosis
1Medizinische Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany. nickenig@med-in.uni-sb.de
Insights
The renin-angiotensin system, particularly angiotensin II acting on AT(1)-receptors, drives atherosclerosis. Inhibiting AT(1)-receptor activation offers promising therapeutic strategies for this vascular disease.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Pharmacology
Background:
- The renin-angiotensin system (RAS) is integral to cardiovascular homeostasis.
- Angiotensin II, a key RAS component, mediates its effects primarily through the angiotensin II type 1 receptor (AT(1)-receptor).
- AT(1)-receptor activation influences vasoconstriction, fluid balance, and neurohumoral control, and also promotes oxidative stress, cellular growth, and apoptosis.
Purpose of the Study:
- To investigate the role of AT(1)-receptor expression and activation in the pathogenesis of atherosclerosis.
- To evaluate the therapeutic potential of targeting AT(1)-receptor pathways in managing atherosclerosis.
Main Methods:
- Review of experimental data and interventional studies.
- Analysis of factors influencing AT(1)-receptor expression, such as oestrogen deficiency and hypercholesterolaemia.
- Assessment of the effects of ACE inhibitors and AT(1)-receptor antagonists on vascular function and atherosclerosis.
Main Results:
- Increased AT(1)-receptor expression, driven by factors like oestrogen deficiency and hypercholesterolaemia, augments angiotensin II actions.
- AT(1)-receptor activation contributes to endothelial dysfunction, increased vascular reactive oxygen species, and promotes atherosclerotic lesion development.
- ACE inhibitors and AT(1)-receptor antagonists demonstrate beneficial effects, including improved endothelial function, reduced blood pressure, and inhibition of atherosclerosis progression.
Conclusions:
- AT(1)-receptor activation is a critical participant in the development and progression of atherosclerosis.
- Targeting AT(1)-receptor activation represents a promising therapeutic strategy for anti-atherosclerotic treatment.
Abstract:
The renin-angiotensin system plays a major role in the pathogenesis of atherosclerosis. Most known effects of angiotensin II are mediated via activation of the AT(1)-receptor, which is in turn influenced to a great degree by levels of expression of the AT(1)-receptor. AT(1)-receptor activation is not only involved in vasoconstriction, water and salt homoeostasis and control of other neurohumoral systems, but also induces reactive oxygen species production, cellular hypertrophy and hyperplasia and apoptosis. Expression of this G-protein-coupled receptor is regulated by multiple factors. Among other conditions, oestrogen deficiency and hypercholesterolaemia increase AT(1)-receptor expression. Experimental data suggest that this augments the actions of angiotensin II, contributes to endothelial dysfunction, increases vascular production of reactive oxygen species, and via these mechanisms promotes atherosclerosis. Because of this, AT(1)-receptor regulation is likely to be critical in the development and progression of vascular lesions. Interventional studies demonstrated that ACE inhibitors which reduce AT(1)-receptor activation, improve endothelial dysfunction and inhibit onset and progression of atherosclerosis. The more specific AT(1)-receptor antagonists have also been shown to decrease blood pressure, protect renal function and to improve endothelial function. Thus, there is compelling evidence that AT(1)-receptor activation participates in the pathogenesis of atherosclerosis, and more importantly, that treatment regimens aiming at inhibition of AT(1)-receptor activation are promising anti-atherosclerotic therapeutic options.