angiotensinogen and Myocarditis

The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS.. In this study, 36 male patients (age: 61.5±2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines.. Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL (r=0.4; p=0.02), AGN (r=0.41; p=0.01), and white blood cells count (r=0.33; p=0.04), whereas it was inversely related to plasma level of adiponectin (r=-.35; p=0.04). After adjustment for covariates, plasma level of ox-LDL (p=0.01) remained significantly associated with SBP (p=0.01). Within the aortic valve, expression of TNF-α was significantly associated with plasma levels of ox-LDL (r=0.58; p=0.03), Ang II (r=0.69; p=0.013), and waist circumference (r=0.60; p=0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II (r=0.51; p=0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-α.. Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.

Topics: Adiponectin; Angiotensin I; Angiotensin II; Angiotensinogen; Aortic Valve Stenosis; Biomarkers; Blood Pressure; Humans; Interleukin-6; Linear Models; Lipoproteins, LDL; Male; Middle Aged; Multivariate Analysis; Myocarditis; Oxidative Stress; Prehypertension; Renin-Angiotensin System; Tumor Necrosis Factor-alpha; Waist Circumference

We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model.. We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats. Blood-pressure- and albuminuria- measurements were monitored during the treatment period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analysis.. Chronic treatment with the antioxidant PDTC decreased blood pressure (162 plus minus 8 vs. 190 plus minus 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 plus minus 0.1 vs. 5.77 plus minus 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 plus minus 0.5 vs. 18.0 plus minus 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-kappaB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-kappaB subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65.. Our data show that inhibition of NF-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-kappaB activation plays an important role in ANG II-induced end-organ damage.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Cardiomegaly; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Heart; Humans; Intercellular Adhesion Molecule-1; Kidney; Models, Animal; Myocarditis; Necrosis; Nephritis; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Proline; Rats; Rats, Sprague-Dawley; Renin; Thiocarbamates; Vascular Cell Adhesion Molecule-1

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Aspirin; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Gene Expression; Heart Diseases; Humans; I-kappa B Kinase; Kidney; Kidney Diseases; Macrophages; Monocytes; Myocarditis; Myocardium; Nephritis; NF-kappa B; Protein Serine-Threonine Kinases; Rats; Renin; Transcription Factor AP-1; Vascular Cell Adhesion Molecule-1