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Angiotensin, LDL peroxidation and atherosclerosis
1Lipid Research Laboratory, Rambam Medical Center, Rappaport Institute for Research in the Medical Sciences and The Bruce Rappaport Technion Faculty of Medicine, Haifa, Israel. skeidar@rambam.health.gov.il
Insights
Hypertension increases low-density lipoprotein (LDL) oxidation, a key factor in atherosclerosis. Angiotensin II (Ang-II) drives this process, but inhibiting Ang-II formation or its receptor may reduce atherosclerosis in hypertensive patients.
Area of Science:
- Cardiovascular Science
- Hypertension Research
- Atherosclerosis Pathogenesis
Background:
- Hypertension is a significant risk factor for atherosclerosis.
- While blood pressure reduction's impact on coronary artery disease is debated, specific interventions show promise in certain populations.
- Elevated plasma renin activity in hypertensive patients correlates with increased myocardial infarction risk.
Purpose of the Study:
- To investigate the relationship between hypertension and low-density lipoprotein (LDL) oxidation.
- To explore the role of angiotensin II (Ang-II) in LDL oxidation and atherogenesis in hypertensive patients.
Main Methods:
- Compared LDL oxidative modification propensity in hypertensive versus normotensive subjects.
- Assessed the effect of Ang-II on macrophage lipid peroxidation and LDL oxidation in vitro and in vivo.
- Investigated the impact of angiotensin-converting enzyme (ACE) inhibitors and an Ang-II receptor antagonist (Losartan) on LDL peroxidation and atherosclerosis in mice.
Main Results:
- LDL from hypertensive patients exhibited increased susceptibility to oxidative modification.
- Ang-II enhanced macrophage lipid peroxidation and LDL oxidation in a dose-dependent manner, mediated by Ang-II receptor binding.
- ACE inhibitors and Losartan significantly reduced LDL peroxidation and atherosclerotic lesions in mice.
Conclusions:
- Angiotensin II plays a crucial role in promoting LDL oxidation and atherogenesis in hypertensive individuals.
- Inhibiting Ang-II formation or blocking its receptor may represent a therapeutic strategy to attenuate atherosclerosis in hypertension.
Abstract:
Hypertension is a known risk factor for the development of atherosclerosis. However, in most of the studies, no effect of blood pressure reduction was demonstrated on the incidence of coronary artery disease, except in the SHEP study in which it was shown that in older persons, with isolated systolic hypertension, antihypertensive stepped-care drug treatment reduced the incidence of total stroke and major cardiovascular event. In hypertensive patients with elevated plasma renin activity, a 5-fold increased incidence of myocardial infarction was demonstrated. As oxidation of low density lipoprotein (LDL) was suggested to be a major risk factor for atherosclerosis, we studied the relationship between hypertension and LDL oxidation. We demonstrated increased propensity of LDL obtained from hypertensive patients to oxidative modification, in comparison with LDL obtained from normotensive subjects and suggested that angiotensin II (Ang-II) may be involved in this effect. Ang-II was shown to enhance macrophage lipid peroxidation both in vivo and in vitro. This effect was dose-dependent and involved the binding of Ang-II to its receptor on the macrophage surface. In addition, these lipid peroxidized Ang-II-treated macrophages could substantially oxidize LDL. Ang-II was shown to possess additional atherogenic properties such as increasing the activity of the macrophage oxidized LDL receptors. It also binds to LDL, thus leading to the formation of a modified lipoprotein, which is taken up by macrophages at enhanced rate through the scavenger receptor. Inhibition of Ang-II formation by angiotensin converting enzyme inhibitors reduced LDL peroxidation in hypertensive patients as well as in the atherosclerotic apo E deficient mice. The reduction in LDL peroxidation in these mice was accompanied by a 70-90% reduction in the atherosclerotic lesion area. A similar effect in these mice was demonstrated with the Ang-II receptor antagonist, Losartan. Thus, we suggest that Ang-II is involved in the development of atherogenesis in hypertensive patients and inhibition of Ang-II formation or prevention of its interaction with its receptor may attenuate the atherosclerotic process.