Protective Effects of Angiotensin II Interruption: Evidence for Antiinflammatory Actions

Nigel J. Dagenais, B.Sc.(Pharm.); Fakhreddin Jamali, Ph.D.

Disclosures

Pharmacotherapy. 2005;25(9):1213-1229. 

In This Article

Angiotensin II as a Proinflammatory Mediator

Angiotensin II is the major effector molecule produced from the renin-angiotensin-aldosterone system; it is produced from the conversion of the inactive angiotensin I by ACE. Angiotensin II exerts vasoconstrictive, growth, and remodeling effects primarily through activation of the angiotensin II type 1 (AT1) receptors.[33] Although the effect of angiotensin II on increasing blood pressure and inducing sodium and water retention through aldosterone secretion is well established, focus has recently turned to angiotensin II as a proinflammatory molecule. Increasing evidence suggests that proinflammatory effects of angiotensin II are directly involved in atherosclerosis development and thrombus formation.

Accumulating evidence indicates that AT1 receptor activation has proinflammatory effects. Angiotensin II activates the nicotinamide adenine dinucleotide (reduced form [NADH])-NADH phosphate (reduced form [NADPH]) oxidase system, resulting in production of reactive oxygen species such as superoxide and hydrogen peroxide.[34,35] The NADH-NADPH oxidases are the primary source of reactive oxygen species in the vasculature and are active throughout all layers of the vessel wall.[35] These reactive oxygen species destroy the endothelial vasodilator nitric oxide and impair endothelial vascular relaxation.[36]

In addition, reactive oxygen species can convert low-density lipoprotein (LDL) to the oxidized form (oxLDL). Uptake of oxLDL by macrophages converts them to foam cells, and accumulation of these cells in vascular endothelium is considered the first stage of atherosclerosis.[26,37] Furthermore, recent evidence suggests that oxLDL can act as an autoantigen in atherosclerotic plaque, suggesting that oxLDL may act as a foreign substance to the immune system.[15,38] This theory is supported by the discovery of oxLDL-reactive T cells in human plaque[15] and by data showing a relationship between oxLDL antibody levels and extent of atherosclerosis.[38] Thus, angiotensin II may have an important role in the initial development of atherosclerosis through oxLDL formation and by contributing to the source of autoantigens in the plaque.

Of interest, many cardiovascular diseases, such as hypertension, diabetes, and heart failure, are associated with activated NADH-NADPH oxidases.[39,40] However, the use of antioxidants such as vitamin C, vitamin E, and β-carotene for reducing cardiovascular end points in prospective clinical trials has not been as positive as expected.[41,42] This apparent ineffectiveness of antioxidant therapy may be due to many reasons. First, the dosage and type of antioxidant used in clinical trials have varied significantly. Second, certain patients apparently are resistant to antioxidant therapy whereas others are responsive, and how to delineate which patients will respond has not been determined.[39]

Furthermore, antioxidant therapy has the potential to induce paradoxical increases in oxidative stress. For example, vitamin C supplementation increased DNA damage in healthy volunteers in one study.[43] Nevertheless, epidemiologic studies suggest that dietary intake of fruits and vegetables high in antioxidants evokes at least some benefit in reducing cardiovascular disease and all-cause mortality.[44,45] The ineffectiveness of antioxidant supplementation may imply that more effective antioxidants are needed.

In addition to generation of reactive oxygen species, angiotensin II can have other proinflammatory effects. Activation of AT1 receptors results in nuclear factor (NF)-κ B activation,[46] which is now considered one of the major transcription factors in regulating many of the functions in the vessel wall. The role of NF-κ B in atherosclerosis has been reviewed extensively elsewhere.[47] Of importance, however, NF-κ B activation results in production of various cytokines and adhesion molecules, such as TNF-α, IL-6, IL-8, monocyte chemotactic protein-1, vascular cell adhesion molecule-1, E selectin, and TGF-β.[47,48]

Nuclear factor-κ B also modulates tissue factor, a major initiator of the coagulation cascade. Other important genes regulated by NF-κ B in patients with cardiovascular disease are the matrix metalloproteinases that reduce plaque stability, and plasminogen activator inhibitor-1, which further promotes platelet aggregation and thrombus formation.[47,49] In vitro studies have confirmed the ability of angiotensin II to induce these NF-κ B regulated genes.[48,49,50] Angiotensin II can also downregulate peroxisome proliferator-activated receptors, which have many antiinflammatory effects.[51] Thus, angiotensin II has a direct link to the induction of the inflammatory process.

Activation of NF-κ B is also induced by reactive oxygen species[52] and cytokines like TNF-α.[53] This results in further cytokine production and development of a positive feedback loop, which further amplifies the inflammatory process. Furthermore, endothelial nitric oxide can reduce NF-κ B activity and production of proinflammatory mediators.[36] Therefore, angiotensin II not only has a direct effect on NF-κ B activity through AT1 stimulation and reactive oxygen species production, but also has an indirect effect on endothelial nitric oxide production through reactive oxygen species-mediated destruction. Hence, angiotensin II may be one of the determining mediators of cardiovascular inflammation, cardiovascular disease progression, and induction of thrombotic events (Figure 1).

The role of angiotensin II interruption in preventing nuclear factor-κ B activation and inhibiting acute coronary syndromes (e.g., stroke, myocardial infarction). OxLDL = oxidized form of low-density lipoprotein; ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; TNF-α = tumor necrosis factor-α; MMP = matrix metalloproteinase; PAI-1 = platelet activator inhibitor-1; IL-1 = interleukin-1; IFN = interferon.

An additional proinflammatory mechanism of angiotensin II is induction of aldosterone release. Data suggest that aldosterone plays a significant role in cardiac remodeling, induction of vascular lesions, and recruitment of leukocytes to atherosclerotic lesions.[54] Thus, aldosterone can amplify the proinflammatory process.

Angiotensin II activity on AT1 receptors can also induce several growth and remodeling effects. Angiotensin II stimulation can induce cell proliferation and cell hypertrophy. Conversely, it can act as a growth suppressor by induction of apoptosis or cell differentiation, depending on the type of cell involved and environmental conditions.[55] Cardiac hypertrophy and development of heart failure after myocardial infarction is thought to be mediated partly by angiotensin II.[56] In addition, evidence indicates that hypertrophic activity of angiotensin II on airway smooth muscle cells might be involved in airway remodeling in asthma, contributing to airway hyperresponsiveness.[57] Furthermore, angiotensin II-induced cell proliferation may have oncogenic implications.

One of the most relevant influences of angiotensin II on cell growth in patients with cardiovascular disease is its effects on angiogenesis. The formation of new blood vessels after myocardial infarction is considered an important component of cardiac remodeling. However, the capacity for angiogenesis after myocardial infarction is generally considered limited and is inadequate to preserve functional myocardium.[58,59] Enhanced angiogenesis may represent a novel therapeutic modality for improving cardiac function after myocardial infarction.

A major angiogenic factor affected by angiotensin II is vascular endothelial growth factor, which activates angiogenesis in many different tissues. However, experimental evidence of angiotensin II in mediating angiogenesis is conflicting and seems highly dependent on the model used. Nonetheless, most experimental data suggest that angiotensin II is proangiogenic.[59] Small clinical trials involving intracoronary infusion of proangiogenic agents like vascular endothelial growth factor in patients with coronary artery disease have shown mixed results.[60] However, some modes of delivery to the heart using longer-acting formulations have shown some clinical benefit in terms of improvement in size of heart defect and reduction in angina attacks.[60] Notwithstanding, larger phase III trials are needed to confirm these results.

Neovascularization, however, is not always beneficial as discussed for cardiac remodeling. Enhanced vessel formation in atherosclerotic plaque can promote plaque development. In addition, angiogenesis in cancer is associated with tumor growth and spread of the disease. In rheumatoid arthritis, angiogenesis contributes to disease development.[61] Furthermore, in diabetes mellitus, excessive neovascularization contributes to development of retinopathy, whereas reduced angiogenesis contributes to poor wound healing and diabetic neuropathy.[58]

In summary, angiogenesis plays a different role in various diseases, and the role of angiotensin II in this process is still inconclusive; therefore, further study is warranted.

Angiotensin II may also have proinflammatory implications in rheumatoid arthritis. Macrophages, for example, express AT1 receptors and produce angiotensin II by ACE.[62,63] Furthermore, elevated ACE activity is found in nodules[64] and synovium[65] in patients with rheumatoid arthritis, and AT1 receptors have appeared in human synovium.[66] Evidence also suggests that angiotensin II regulates immune responses by using a calcineurin-dependent pathway through AT1 receptors, indicating a direct effect on T cells.[67] Therefore, angiotensin II may have direct involvement in the induction and progression of rheumatoid arthritis.

The NF-κ B pathway is also an important target in patients with rheumatoid arthritis; human synovial biopsies demonstrate elevated NF-κ B concentrations and activity.[68,69] Furthermore, anti-TNF-α therapy in these patients has proven invaluable,[70] which may be explained partly by reduced NF-κ B activation in the joints. One author has referred to NF-κ B as the "holy grail" for rheumatoid arthritis.[71] This pathway is now considered the central regulator of cellular processes throughout tissues[52] and likely contributes to the pathogenesis of numerous diseases in humans, such as cancer, asthma, and Alzheimer's disease.[72] Many researchers are aggressively investigating potential inhibitors of this pathway, one of which may involve angiotensin II interruption.

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