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Published on: September 28, 2015
Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A
Alan Daugherty1, Debra L Rateri, Hong Lu
1Division of Cardiovascular Medicine, Wethington Building, Room 521, University of Kentucky, Lexington, KY 40536-0200, USA. alan.daugherty@uky.edu
Insights
Hypercholesterolemia worsens atherosclerosis by increasing angiotensin peptides. Blocking the AT1A receptor significantly reduces this effect, revealing a key mechanism in disease progression.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Atherosclerosis Research
Background:
- Hypercholesterolemia-induced atherosclerosis is lessened by AT1 receptor antagonism or deficiency.
- The mechanism behind the significant impact of angiotensin II (Ang II) antagonism remains unclear.
- This study investigates if hypercholesterolemia boosts angiotensin peptide production, explaining the effects of AT1A receptor deficiency.
Purpose of the Study:
- To determine the mechanism behind the pronounced effect of AT1A receptor deficiency on atherosclerosis.
- To investigate if hypercholesterolemia stimulates angiotensin peptide production.
- To establish a rationale for the observed impact of AT1A receptor deficiency on atherogenesis.
Main Methods:
- Analysis of atherosclerotic lesions in LDL receptor-deficient mice.
- Immunocytochemical analysis to identify components of the Ang II synthesis pathway within lesions.
- Assessment of lesion size, composition, systolic blood pressure, oxidation, and chemoattractants in wild-type and AT1A receptor-deficient mice.
- Measurement of aortic AT2 receptor mRNA expression and effects of AT2 receptor deficiency.
- Quantification of plasma angiotensinogen and angiotensin peptides in hypercholesterolemic and AT1A receptor-deficient mice.
Main Results:
- AT1A receptor deficiency significantly reduced atherosclerotic lesion size in both male and female mice.
- Reductions in atherosclerosis were independent of blood pressure, oxidation, and chemoattractants.
- Hypercholesterolemia markedly increased systemic angiotensinogen and angiotensin peptides (Ang II, III, IV, 4-8).
- These increases in angiotensin peptides were abolished in hypercholesterolemic AT1A receptor-deficient mice.
- AT2 receptor expression and deficiency did not significantly affect lesion area or composition.
Conclusions:
- AT1A receptor deficiency markedly reduced hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice.
- Hypercholesterolemia is associated with increased systemic angiotensin peptides.
- AT1A receptor deficiency mitigated the hypercholesterolemia-induced increase in angiotensin peptides.
- This study demonstrates that hypercholesterolemia stimulates angiotensin peptide production, explaining the significant benefit of AT1A receptor deficiency in reducing atherosclerosis.
Background:
Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT1 receptors or AT1A receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT1A receptor deficiency on atherogenesis.
Methods And Results:
Atherosclerotic lesions were analyzed in LDL receptor-deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT1A receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT2 receptor mRNA expression was not altered in AT1A receptor-deficient mice, and AT2 receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4-8). These increases were ablated in hypercholesterolemic AT1A receptor-deficient mice.
Conclusions:
AT1A receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT1A receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT1A receptor deficiency in reducing atherosclerosis.
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