Role of the Renin-Angiotensin-Aldosterone System and Proinflammatory Mediators in Cardiovascular Disease

Ferrario, Carlos M.; Strawn, William B.

doi:10.1016/j.amjcard.2006.01.059

Cited by 450 publications

(372 citation statements)

References 53 publications

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“…In addition, altered renal expression of AT1 precedes the development of renal fibrosis in aging rats (Schulman et al 2010). Ang II, an important vascular constrictor, is recognized as a potent pro-inflammatory mediator that participates in vascular inflammatory responses (Ferrario and Strawn 2006;Muller et al 2000;Ruiz-Ortega et al 2000). It seems clear that the production of RS and the activation of transcription factor NF-κB play major roles in the intracellular signaling pathways involved in RAS and Ang II-induced inflammation (Ungvari et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Kim

Heo

et al. 2011

AGE

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Angiotensin II (Ang II), a major effector of the renin-angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor-κB (NF-κB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-κB activation are not fully understood. The purpose of this study was to document altered molecular events involved in agerelated changes in Ang II signaling and NF-κB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-κB by phosphorylating IκBα and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IκB kinase αβ, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-κB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Kim

Heo

et al. 2011

AGE

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“…8 This modulation of the renin-angiotensin-aldosterone system, in addition to decreasing blood pressure, decreases inflammation at the level of the vascular endothelium, thus limiting progression of atherosclerosis. 9 The mechanism by which atorvastatin increases vitamin D levels is related to inhibition of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase. Cholesterol is synthesized from 7-dehydrocholesterol, which is also a precursor of vitamin D 3 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Atorvastatin on Vitamin D Levels in Patients With Acute Ischemic Heart Disease

Pérez‐Castrillón¹,

Vega²,

Abad³

et al. 2007

The American Journal of Cardiology

151

104

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Vitamin D deficiency is a risk factor for osteoporosis and other chronic diseases, including type 1 diabetes, hypertension, metabolic syndrome, and ischemic heart disease. Cholesterol and vitamin D share the 7-dehydrocolesterol metabolic pathway. This study evaluated the possible effect of atorvastatin on vitamin D levels in patients with acute ischemic heart disease. Eighty-three patients (52 men and 31 women) with an acute coronary syndrome (75 with acute myocardial infarction and 8 with unstable angina) were included. After diagnosis, patients received atorvastatin as secondary prevention. Serum vitamin D was measured by high-performance liquid chromatography at baseline and at 12 months. Atorvastatin treatment produced a statistically significant decrease in cholesterol and triglyceride levels and an increase in vitamin D levels ( Vitamin D deficiency is a risk factor for osteoporosis and other chronic diseases, including type 1 diabetes, hypertension, metabolic syndrome, and ischemic heart disease. 1 Vitamin D is synthesized in the skin by ultraviolet radiation that acts on 7-dehydrocolesterol, which is hydroxylated into carbon-25 by 25-hydroxyvitamin D-1␣ hydroxylase or CYP27B1, an enzyme located in the mitochondria of the hepatocyte. The resulting metabolite, 25-hydroxyvitamin D, is the best way to measure individual vitamin D levels. 2 Cholesterol and vitamin D share the 7-dehydrocolesterol metabolic pathway. 3 Statins have beneficial effects on morbidity and mortality of patients with acute ischemic heart disease; these may be mediated by vitamin D. These patients have a greater prevalence of vitamin D deficiency and are often treated with statins as secondary prevention. 1 This led us to study the possible effect of atorvastatin on vitamin D levels in this group of patients. Increased levels of vitamin D could explain some of the beneficial effects of atorvastatin at the cardiovascular and bone metabolism levels that are unrelated to cholesterol levels. Methods and ResultsPatients hospitalized for an acute coronary syndrome, defined as high-risk unstable angina, non-ST-elevated myocardial infarction, or ST-elevated myocardial infarction, were eligible for inclusion. Eighty-three patients (52 men and 31 women) with an acute coronary syndrome (75 with acute myocardial infarction and 8 with unstable angina) were included. Patients were recruited at hospital admission. Exclusion criteria were alcoholism, neoplasia, hyperor hypocalcemia, and treatment with phosphocalcium metabolism-modifying drugs. After diagnosis, patients received atorvastatin as secondary prevention. Low (10 to 20 mg) and high (40 to 80 mg) doses were used according to baseline levels of cholesterol and triglycerides and index of vascular risk. Only patients completing follow-up were evaluated. A control group of 73 hypertensive patients (38 men and 35 women) not receiving treatment with statins was included.Blood samples were obtained after 8 or 9 hours of fasting. Total calcium, phosphorus, total cholesterol, and triglycerides were mea...

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“…A previously reported accelerated development of atherosclerotic CVD (24) and vascular calcification (24) in uremia may also contribute. The target of ACE inhibition, angiotensin II, is itself an important inducer of vascular injury in several inflammatory settings other than uremia (25), where it induces endothelial dysfunction (25) and CRP generation (26), enhances vascular remodeling (25), and accelerates the progression of atherosclerosis (25). Finally, a reverse causality, whereby lower BP and/or normalization of hyperglycemia in ACEI-treated patients leads to lower levels of systemic inflammation cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Effect of Renin Angiotensin System Blockade on Pentraxin 3 Levels in Type-2 Diabetic Patients With Proteinuria

Yılmaz

Axelsson²,

Sönmez³

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: Long pentraxin 3 (PTX3) is a multimeric inflammatory mediator. Increased serum PTX3 levels have been reported among end-stage renal disease patients. Moreover, PTX3 has been suggested to represent a novel mortality risk factor, and elevated PTX3 levels have been shown to accompany increased albuminuria among patients with chronic kidney disease (CKD).Design, setting, participants, & measurements: We analyzed data of 49 persons with stage 1 diabetic CKD and 32 healthy subjects in a prospective controlled trial. Endothelial dysfunction was determined by flow-mediated dilation (FMD). Serum PTX3, high-sensitivity C-reactive protein (hs-CRP) levels, and FMD were studied in baseline and after 12 wk of ramipril therapy. Stepwise multivariate regression analysis evaluated the association of FMD with clinical and serologic parameters.Results: Serum PTX3, hsCRP, and albumin levels and proteinuria were significantly decreased, and FMD levels were significantly increased, after ramipril treatment. FMD was negatively correlated with serum PTX3, 24-h proteinuria, and hsCRP levels and positively correlated to serum albumin both at baseline and after the 12-wk treatment period. Multivariate regression analysis revealed that PTX3 levels were independently related to FMD both before and after ramipril treatment.Conclusions: Our study shows that serum PTX3 levels are associated with endothelial dysfunction in patients with stage 1 diabetic CKD, independent of CRP. In addition, short-term ACE-inhibitor treatment significantly improves FMD and normalizes PTX3, hsCRP, and urinary protein excretion. (NCT: The study was registered in clinicaltrials.gov as NCT00674596.) Clin

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Role of the Renin-Angiotensin-Aldosterone System and Proinflammatory Mediators in Cardiovascular Disease

Cited by 450 publications

References 53 publications

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Effects of Atorvastatin on Vitamin D Levels in Patients With Acute Ischemic Heart Disease

Effect of Renin Angiotensin System Blockade on Pentraxin 3 Levels in Type-2 Diabetic Patients With Proteinuria

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