Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component

Serneri, Gian Gastone Neri; Boddi, Maria; Modesti, Pietro Amedeo; Coppo, Mirella; Cecioni, Ilaria; Toscano, Thomas; Papa, Maria Letizia; Bandinelli, Manuela; Lisi, Gianfranco; Chiavarelli, Mario

doi:10.1161/01.res.0000130944.49657.b8

Cited by 55 publications

(33 citation statements)

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“…The RAS elicits inflammatory responses in several tissues (12,35,36). As previously reported (7,11,34), there was cellular infiltration into the air spaces associated with meconiuminduced increases in AT 1 R and activation of the tissue RAS.…”

Section: Discussionsupporting

confidence: 62%

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

et al. 2008

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ABSTRACT:The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT 1 R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT 1 R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT 1 R protein approximately 3-fold (p ϭ 0.006), mRNA 29% (p ϭ 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT 1 R expression Ͼ3-fold in cultured type II pneumocytes and caused concentrationdependent cell death inhibited by losartan. Meconium increases AT 1 R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT 1 R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression. T he fetal excretion of meconium into the amniotic fluid occurs in 18 -20% of near-term and term pregnancies and is associated with intra-uterine stress (1-5). When episodes are severe, fetal respiratory efforts are altered and meconium contaminated amniotic fluid may be inhaled before, at the time of, or soon after birth in approximately 5% of neonates. These neonates may develop pneumonitis and lung injury secondary to meconium aspiration syndrome (MAS) (2,3,5,6). Thirty percent of neonates with MAS require mechanical ventilation, and many develop respiratory failure requiring inhaled nitric oxide, high-frequency ventilation, or extracorporal membrane oxygenation. It is unclear, however, what contributes to the pathogenesis and severity of MAS.The clinical manifestations of MAS reflect airway obstruction due to inhaled particulate matter and development of chemical pneumonitis and inflammation, which contribute to the severity of MAS (5). Inflammatory cytokines are elevated in the blood of newborn piglets and the tracheal lavage and lungs of animals after pulmonary instillation of meconium (5,7-10). In most animal studies, homogenized meconium containing particulate matter was instilled into the lungs, making it difficult to separate the obstructive and inflammatory components. We (7) removed the obstructive effects of the particulate matter by using a sterile filtrated supernatant from homogenized term human meconium (MS). In newborn rabbits, MS caused pulmonary inflammation, neutrophil migration, epithelial cell apoptosis, and activation of the pulmonary renin-angiotensin system (RAS) ...

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Section: Discussionsupporting

confidence: 62%

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

et al. 2008

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“…Angiotensin II activates transcription of "calcificationrelated" genes: parathyroid hormone receptor, bone morphogenic protein 2, and bone-liver-kidney-alkaline phosphatase genes in the coronary artery vascular smooth muscle cells (41). These effects seem to be parallel to RAS influence on the other mechanisms of coronary atherosclerosis development, including vascular smooth muscle proliferation, intimal fibrosis, chemoattraction of inflammatory cells, increase of plasminogen activator inhibitor-1 expression, and lipid accumulation/atherogenecity (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we did not measure the activity of ACE and protein plasma levels of other components of the RAS, because it is broadly accepted that activity of the renin-angiotensin tissue system rather then systemic effects are responsible for the structural and functional perturbations that occur in CAD (42,43).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis

Krętowski

McFann

Hokanson³

et al. 2007

Diabetes

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Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5-29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6 -388], P ‫؍‬ 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes. Diabetes 56:863-871, 2007 P atients with type 1 diabetes have a dramatically higher risk of coronary artery disease (CAD) compared with the general population (1,2). Coronary artery calcification (CAC), a marker of coronary artery plaque burden, correlates very well with the established CAD risk factor profile in patients with type 1 diabetes (3-5). There is growing evidence that CAC strongly predicts future coronary events in asymptomatic nondiabetic and diabetic subjects (4 -6).Diabetic nephropathy plays an important role in the pathogenesis of advanced CAD in type 1 diabetes (2). However, little is known concerning determinants of subclinical atherosclerosis detected as rapidly progressing CAC. Activation of the renin-angiotensin system (RAS) by hyperglycemia may be the key mechanism (7,8). The RAS involves enzymatic processing of angiotensinogen (AGT) to angiotensin I, further cleaved by ACE to angiotensin II. Treatment with ACE inhibitors lowers the risk of cardiovascular death, myocardial infarction, and coronary revascularization in the general population and in diabetic patients (9 -11).The RAS activity is modified by variants of the genes coding functional proteins of this pathway (12-14). The AGT gene, localized on chromosome 1q41-qter, encodes AGT. There is only one haplotype block at the AGT locus, and all common single nucleotide polymorphisms (SNPs) identified appear to be in complete linkage disequilibrium with the most intensively studied M235T polymorphism (13,15). Although the functional variant has not yet been definitively identified (16), the T235 allele has been consistently associated with cardiovascular disease (13,17) and ...

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“…Ventricular biopsy samples from the unstable angina patients showed numerous lymphocytes, macrophages, and endothelial cells, and they had overexpression of angiotensinogen, ACE, and AT 1 receptor genes as well as up-regulation of tumor necrosis factor-␣, interferon-␥, and iNOS, indicating that locally generated ANG II seems to amplify the immuno-mediated inflammatory process of coronary microvessels occurring in unstable angina (Neri Serneri et al, 2004).…”

Section: A Coronary Blood Flow Responsementioning

confidence: 96%

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

2007

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Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component

Cited by 55 publications

References 50 publications

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

Meconium Increases Type 1 Angiotensin II Receptor Expression and Alveolar Cell Death

Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

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