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Regulation of the angiotensin AT1 receptor expression by hypercholesterolemia
1Klinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Str. 9, Köln D-50924, Germany.
Insights
High cholesterol and LDL levels increase AT1 receptor expression in blood vessels. This enhances the effects of angiotensin II, contributing to cardiovascular disease progression.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Molecular Biology
Background:
- The angiotensin II type 1 (AT1) receptor is central to angiotensin II's biological actions, implicating it in hypertension and arteriosclerosis.
- Hypercholesterolemia is a significant risk factor for cardiovascular diseases, with prior studies suggesting interactions between the renin-angiotensin system and lipid metabolism.
Purpose of the Study:
- To investigate the effects of low-density lipoprotein (LDL) and hypercholesterolemia on AT1 receptor expression and function.
- To elucidate the molecular mechanisms linking hypercholesterolemia to enhanced vascular responsiveness to angiotensin II.
Main Methods:
- In vitro studies using cultured vascular smooth muscle cells to assess AT1 receptor gene expression and functional responses to angiotensin II.
- In vivo studies in hypercholesterolemic rabbit models to evaluate vascular AT1 receptor expression and angiotensin II-induced vasoconstriction.
Main Results:
- LDL exposure led to increased AT1 receptor gene expression and enhanced functional responses in cultured vascular smooth muscle cells.
- Hypercholesterolemic rabbits exhibited approximately twofold higher vascular AT1 receptor expression compared to normocholesterolemic controls.
- This elevated receptor expression resulted in enhanced angiotensin II-induced vasoconstriction in hypercholesterolemic rabbits.
Conclusions:
- Hypercholesterolemia and elevated LDL concentrations up-regulate vascular AT1 receptor expression, potentiating the renin-angiotensin system's biological activity.
- This lipid-induced AT1 receptor upregulation plays a pathophysiologically significant role in cardiovascular disease, potentially explaining the benefits of renin-angiotensin system blockade in hypercholesterolemic conditions.
Abstract:
The AT1 receptor mediates most of the biological effects of angiotensin II and has therefore been implicated in the pathogenesis of hypertension as well as arteriosclerosis. Hypercholesterolemia is a prominent risk factor for the development of these cardiovascular diseases. Since experimental results from hyperlipidemic animal models suggested an interaction of the renin-angiotensin system and hypercholesterolemia, the effects of low-density lipoprotein (LDL) and hypercholesterolemia has recently been investigated in vitro and in vivo. LDL causes in cultured vascular smooth muscle cells an up-regulation of AT1 receptor gene expression which is followed by an enhanced functional response upon stimulation with angiotensin II. This effect is also evident in vivo, as assessed in hypercholesterolemic rabbits. The vascular AT1 receptor expression is increased approximately twofold in hypercholesterolemic rabbits in comparison to normocholesterolemic animals. This leads ultimately to an enhanced angiotensin II-induced vasoconstriction. Thus, hypercholesterolemia and elevated concentrations of LDL enhance AT1 receptor expression in the vasculature causing an enhanced biological effectiveness of the renin-angiotensin system. This interaction may explain that blockade of the renin-angiotensin system attenuates the progress of arteriosclerosis in the hypercholesterolemic organismen and indicates a pathophysiologically important role for the lipid-induced AT1 receptor up-regulation.