How exciting it is to see a field so well established as the ren- angiotensin system continue to grow and mature. Originally, following the original identification of.
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- The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling
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Intracardiac intracellular angiotensin system in diabetes. Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization. High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets. Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology Mark J. Osborn , Beau R. Braunlin Journal of Inherited Metabolic Disease Share your thoughts with other customers.
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See our Returns Policy. Visit our Help Pages. Audible Download Audio Books. Since the rate-limiting step of RAAS is under the control of renin, the idea of inhibiting renin to suppress RAAS was suggested in the mids, but the development of rennin inhibitors was a long and difficult process [ 7 ]. Likewise, the first oral DRI, aliskiren, was marketed in for the treatment of hypertension [ 8 ]. Another effector of the RAAS, aldosterone, exerts important endocrine functions by regulating fluid volume, sodium and potassium homeostasis, and primarily acting in the renal distal convoluted tubules. Production of aldosterone is under the regulation of angiotensin II, hyperkalemia, adrenocorticotropic hormone ACTH , and sodium level [ 9 ].
Clinical trials have shown that blocking aldosterone receptors with mineralocorticoid receptor antagonists MRA , spironolactone or eplerenone, reduces blood pressure, lowers albuminuria, and improves the outcome of patients with heart failure or myocardial infarctions or cardiovascular complications associated with diabetes mellitus [ 10 ]. Experimental studies show that Ang II 1—7 is a competitor of Ang II and indeed may have cardiorenal protective effects [ 12 , 13 ].
Ang II is also produced by non-ACE enzymes, such as serine protease chymase, which have been found in the heart, vasculature, and other tissues [ 14 , 15 ]. Inflammation plays a key role in the initiation, progression, and development of an array of cardiovascular diseases such as hypertension, atherosclerosis, restenosis after balloon angioplasty, nephropathy, and cardiomyopathy [ 16 ].
A typical example of how inflammation underlies the development of cardiovascular disease is atherosclerosis, via the activation of endothelial cells by the inflammatory cytokines. Endothelium dysfunction due to injury by the inflammatory process has been associated with cardiovascular risk factors including hypertension, diabetes mellitus, or obesity [ 17 ]. Tumor necrosis factor alpha TNF is a key proinflammatory cytokine regulating the expression of many genes of inflammation, oxidative stress, and antiapoptotic signaling pathways, virtually, in all types of cells [ 18 ].
The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling
Aberrant TNF signaling leads to the development of pathological conditions including cardiovascular disease, and therapeutic blocking of TNF signaling has been proposed for the treatment of several inflammatory diseases particularly rheumatoid arthritis and bowel disease [ 18 ]. TNF impairs endothelium-dependent nitric oxide NO mediated vasorelaxation in coronary arteries or carotid artery via superoxide radical production [ 19 ]. Patients with high levels of circulating TNF have a greater risk of developing cardiovascular disease [ 20 ].
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Deletion of TNF in mice inhibits intimal hyperplasia after carotid artery injury [ 22 ], while an increased expression of TNF aggravates pulmonary hypertension in mice [ 23 ]. TNF mediated inflammation plays an important role in vascular remodeling. Human carotid artery smooth muscle cells respond to TNF with increased cell proliferation, whereas inhibition of circulating TNF prevents carotid artery postinjury media remodeling and neointima formation in rats [ 24 ].
TNF inhibition has been shown to improve endothelium function via stimulating endothelial cells regeneration [ 25 ]. Activated NF- B induces vascular smooth muscle cells proliferation and mediates neointima hyperplasia after vascular injury [ 27 ]. Another marker of inflammation is C-reactive protein CRP. CRP is considered a hallmark of the acute-phase response and a predictor of cardiovascular event risk [ 28 ]. C-reactive protein is mainly produced in the liver [ 29 ], but other cell types such as smooth muscle and endothelial cells of atherosclerotic arteries show CRP expression [ 30 ].
CRP plays a role in mediating vascular disease. In vitro studies show that CRP has proinflammatory and prothrombotic effects [ 31 ], inhibits endothelial progenitor cell differentiation and function [ 32 ], and upregulates AT1R [ 33 ]. CRP activates classical complement signaling cascade, which plays a key role in neointima formation in injured vessels [ 34 ]. Circulating CRP levels correlate with several inflammation markers including inflammatory cytokines, cell adhesion molecules, markers of activated platelets, and white cells [ 35 ].
All of these inflammation markers are also predictive of coronary artery events [ 36 ].
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Interleukin-6, a pleiotropic cytokine, regulates many cellular functions including proliferation and apoptosis. IL-6 plays an important role in inflammation and modulates the development of several diseases including cardiovascular disease such as hypertension and other related diseases. High circulating levels of IL-6 are found in hypertensive patients. Type I diabetic rats have high circulating levels of IL-6 and increased blood vessel contractility [ 37 ]. IL-6 overexpression in mice induces pulmonary vascular remodeling that is similar to that seen in patients with pulmonary hypertension and induces pulmonary hypertension via proliferative and antiapoptotic mechanisms [ 38 ].
IL-6 also modulates vascular reactivity. Treatment of isolated human blood vessels from various organs with IL-6 results in increased contraction [ 39 ]. IL-6 mediates the development of vascular occlusive disease and is a predictor of cardiovascular sudden death [ 40 ]. IL-6 effects on vascular system are mediated via NF- B signaling, which plays a key role in vascular remodeling. Inflammation-mediated injury to endothelium generates a pronflammatory signaling cascade and the expression of intercellular adhesion molecule-1 ICAM-1 and vascular cell adhesion molecule-1 VCAM-1 , both of which recruit blood monocytes to vascular wall, thus perpetuating the release of more cytokines and chemokines at injury site culminating with development of vascular disease such as atherosclerosis.
VCAM-1 expression is upregulated by Ang II in rat aorta, whereas spironolactone, an antagonist of mineralocorticoid receptors, inhibits VCAM-1 and other inflammatory markers expression [ 43 ].
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RAAS plays a crucial role in the initiation and maintenance of vascular inflammation and vascular remodeling. Vascular inflammation leads to endothelium dysfunction, and a decreased endothelial function mediates progression of cardiovascular disease. A dysfunctional endothelium is leaky and facilitates migration of inflammatory cell into the vascular wall and stimulates smooth muscle cells proliferation, processes that decrease vascular function and promote development of cardiovascular disease and tissue injury.
A dysfunctional endothelium provides proinflammatory environment in such as it promotes recruitment and attachment of inflammatory cells, which are well known to play a key role in atherosclerosis. There is increasing evidence indicating a link between hypertension and atherosclerosis via Ang II mediated inflammation. In vivo , acute treatment with Ang II significantly increases leukocytes adhesion in the rat mesenteric arteries [ 46 ].
Animal and human studies show that Ang II has proinflammatory responses in arteries, heart, and kidney by regulating the expression of cytokines and chemokines. In vitro treatment of rat vascular smooth muscle cells with Ang II upregulates MCP-1, and blockade of AT1R with losartan prevents MCP-1 expression and monocytes migration into vessel wall and other target organs [ 50 ]. Although a vasoconstrictor, Ang II induces endothelial damage by inhibiting endothelial cells regeneration.
Ang II acts as a second messenger to activate intracellular signaling pathways such as mitogen-activated protein kinase MAPK and AKT, pathways that mediate cell proliferation and apoptosis and thereby vascular dysfunction [ 51 ]. Ang II plays a significant role in the initiation and progression of atherogenesis, an inflammation mediated process. In injured arteries, Ang II provides a positive feedback loop in vascular inflammation via recruitment of inflammatory cells, which then produce more Ang II, therefore perpetuating vascular inflammation [ 1 ].
Ang II is a potent prooxidant. Ang II-mediated oxidative stress reduces nitric oxide NO level and activates redox sensitive genes, particularly cytokines, adhesion molecules, and matrix metalloproteinases [ 53 ]. Ang II is also a profibrotic factor. Chronic infusion of mice with Ang II results in increased blood pressure, infiltration of inflammatory cells into myocardium, and cardiac fibrosis [ 54 ].
Chronic treatment of rat aortic smooth muscle cells with Ang II induces cell hypertrophy by increasing protein synthesis [ 56 ].
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Ang II-treated rat cardiac fibroblasts display increased expression of focal adhesion kinases FAK and integrins, whereas cardiac myocytes express high levels of c-fos, EGFR1, TGF , and extracellular matrix proteins , Inflammation mediates endothelial injury which alters endothelial cell architecture so that the endothelium becomes dysfunctional.
It has been shown that a dysfunctional endothelium is directly associated with hypertension and atherosclerosis [ 17 ]. A functional endothelium is a key regulator of NO release, and loss of NO bioavailability is associated with high level of Ang II via oxidative stress. Although development of atherosclerosis is a multifactorial complex process, interaction between endothelial dysfunction and oxidative stress plays an important role in atherosclerotic process. Increased oxidative stress within the vascular wall is a hallmark of vascular disease such as atherosclerosis, hypertension, and diabetes.
Indeed, high level of superoxide is an important factor in atherosclerosis initiation by recruitment of inflammatory cells and endothelial dysfunction. Total genetic deletion of NADPH oxidase subunit, Nox2, in mice results in significant decrease of aortic atherosclerosis [ 57 ].
NO has protective effects on cardiovascular and renal systems. NO effects on the vasculature are numerous from inducing vasodilatation of all types of blood vessels to inhibiting platelet aggregation and adhesion or leukocytes adhesion to endothelium. Furthermore, NO inhibits DNA synthesis, mitogenesis, and vascular smooth muscle cells proliferation and counteracts oxidative stress [ 59 ].
The proinflammatory and profibrotic effects of the RAAS are also mediated by aldosterone. Aldosterone plays a role in organ fibrosis and tissue ischemia, and in conjunction with macrophages, it induces cardiac fibrosis [ 60 ]. Aldosterone promotes insulin resistance and vascular remodeling and influences the development of atherosclerosis [ 61 ].