Interaction of Dyslipidemia and Renin-Angiotensin System (RAS)
Interactions between dyslipidemia and activation of neurohumoral systems, such as RAS, may not only explain the frequent coexistence of hypertension and dyslipidemia, but also play an important role in the pathogenesis of atherosclerosis. Experimental data suggest that the effects of Ang II and lipo-proteins on atherogenic risk are not independent and that the pathways by which Ang II and dyslipidemia lead to vascular disease may frequently overlap. There is a suggestion that the combined use of cholesterol-lowering drugs along with agents that modulate RAS may have additive benefits in the prevention and treatment of coronary artery disease, hypertension, and heart failure.
Keidar et al.  harvested macrophages from the peritoneum after injection of Ang II in the rat, and observed that Ang II dramatically increased macrophage cellular cholesterol biosynthesis with no significant effect on blood pressure or on plasma cholesterol levels. Fosinopril and the AT1 receptor blocker (losartan) decreased cholesterol biosynthesis in response to Ang II. Further, in cells that lack the ATI receptor (RAW macrophages), Ang II did not increase cellular cholesterol synthesis, thereby confirming the role of ATI receptor in Ang II-mediated cholesterol synthesis by macrophages.
Increased oxidative stress is regarded an important feature of hypercho-lesterolemic atherosclerosis. LDL enhances Ang II AT1 receptor expression in cultured SMCs, and atherosclerotic lesions are associated with increased an-giotensin-converting enzyme (ACE) expression, which may serve as a source of local production of Ang II and ultimately increased stimulation of superoxide anion production. Experimental studies have shown that dyslipidemia activates RAS. All components of increased RAS activation have been identified in hyperlipidemic atherosclerotic lesions. These include, in particular, increased expression of ACE and ATI receptor . A number of recent studies in human atherosclerotic tissues have confirmed the upregulation of ACE and AT1 receptors, particularly in the regions that are prone to plaque rupture. Importantly, these same areas show extensive inflammatory cell deposits, macrophage accumulation, and apoptosis.
In vitro studies have shown that incubation of vascular SMCs with LDL increases expression of the ATI receptors. Li et al.  in our laboratory examined the expression of Ang II receptors in human coronary artery endothelial cells and observed that ox-LDL increases the mRNA and protein for ATI, but not AT2, receptors, implying that ox-LDL increases ATI expression at the transcriptional level. In this process, activation of the redox-sensitive transcription factor NF-kB plays a critical role. In recent studies, we showed that ox-LDL also enhances ACE expression in human coronary artery endothelial cells.
The association of hypertension with hyperlipidemia has been noted in population studies as well. The prevalence of hypertension is greater in populations with high cholesterol. Sung et al.  examined the blood pressure response to a standard mental arithmetic test in 37 healthy normotensive subjects with hypercholesterolemia and 33 normotensive subjects with normal cholesterol levels. The blood pressure response during the arithmetic test was significantly higher in the hypercholesterolemic group compared to the nor-mocholesterolemic group. In a double-blind, crossover design, treatment with statins was associated with lower mean systolic blood pressure prior to and during the arithmetic test. These observations suggest that individuals with hypercholesterolemia have exaggerated systolic blood pressure responses to mental stress, and the lipid lowering improves systolic blood pressure response to stress. Nazzaro et al.  made an interesting observation of combined and distinct effects of ACE inhibitors and statins on blood pressure. They examined the effects of lipid lowering on blood pressure in a study of 30 subjects with coexisting hypertension and hypercholesterolemia. The combination of statins and ACE inhibitor achieved greater blood pressure reduction than either alone.
To define the relationship of RAS and lipids in humans, Nickenig et al.  administered Ang II in normocholesterolemic and hypercholesterolemic men and found that blood pressure was exaggerated in the hypercholesterol-emic group and this response could be blunted by LDL cholesterol-lowering agents. Further, these investigators found that there was a linear relationship between AT1 receptor density on platelets and LDL cholesterol concentration in plasma. Further, treatment with statins decreased AT1 receptor density. Statin-mediated downregulation of AT1 receptor expression has also been shown in vascular SMCs. A recent study has indeed shown that statins directly decrease AT1 receptor expression in endothelial cells.
Atherosclerosis is inhibited by fosinopril and losartan in animal studies, suggesting that the antiatherosclerotic effects of RAS inhibitors may be due, at least in part, to direct inhibition of LDL oxidation and other actions of Ang II in the vessel wall. In order to examine the direct contribution of RAS in dyslipidemic atherosclerosis, we recently conducted a study in apoE knockout mice fed a high cholesterol diet. Treatment of these animals with cande-sartan, an ATI receptor blocker, decreased the extent of atherosclerosis as did the treatment with the potent HMG-CoA reductase inhibitor rosuvastatin. More importantly, we observed that concurrent therapy with candesartan and rosuvastatin almost completely abolished atherogenesis. In concert with prevention of atherogenesis, the animals treated with the combination of anti-hypertensive and anti-dyslipidemic therapy had ablation of inflammatory signals - ICAM-1, VCAM-1, MCP-1, CD40/CD40L and expression of LOX-1.
These findings unarguably suggest a mutually facilitative interaction between dyslipidemia and RAS in relation to atherogenesis and development of hypertension. These observations also suggest that inflammatory signals are also related to dyslipidemia and RAS activation. Notably, a similar interaction between altered biosynthesis of NO as well as vasoconstrictor autacoids, such as endothelin-1 and leukotrienes, has also been implicated in this vascular dysfunction [36, 37].
Was this article helpful?
Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...