elastin and candesartan

Matrix metalloproteinases, a family of proteolytic enzymes are thought to be involved in extracellular matrix accumulation during development of hypertensive target organ disease. The present study was designed to compare hypertensive patients with normotensive individuals with respect to serum levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and to search for the effect of antihypertensive treatment on the serum enzyme levels.. Thirty-three patients with stage 1 primary hypertension and sixteen age- and sexmatched control subjects were enrolled into the study. Serum MMP-9 and TIMP-1 levels were assessed in the hypertensive group before and after a 3-month-antihypertensive treatment (candesartan 8 mg/day to 17 patients and lisinopril 10 mg/day to 16 patients).. Pre-treatment serum MMP-9 levels were higher in the hypertensive group (p=0.309) while serum TIMP-1 levels were lower (p=0.296). Serum MMP-9 levels were decreased (p<0.001) and TIMP-1 levels were increased (p=0.022) after the antihypertensive treatment.. In hypertensive patients, increased MMP-9 activity could result in increased degradation of elastin relative to collagen and non-elasticity, while decreased TIMP-1 activity could lead to accumulation of poorly cross-linked, immature and unstable fibril degradation products, which result in misdirected deposition of collagen. Our study is important for revealing the role of the MMP enzyme system in the pathogenesis of hypertensive target organ disease.

Topics: Adult; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Collagen; Elastin; Extracellular Matrix; Female; Humans; Hypertension; Lisinopril; Male; Matrix Metalloproteinase 9; Middle Aged; Renin-Angiotensin System; Tetrazoles; Tissue Inhibitor of Metalloproteinase-1

Elastin deficiency causes vascular stiffening, a leading risk for hypertension and chronic kidney disease (CKD). The mechanisms mediating hypertension and/or CKD pathogenesis due to elastin deficiency are poorly understood. Using the elastin heterozygous (Eln+/-) mouse model, we tested whether renal dysfunction due to elastin deficiency occurs independently of and precedes the development of hypertension. We assessed blood pressure and renal hemodynamics in 30-day and 12-week-old male and female mice. At P30, blood pressure of Eln+/- mice was similar to wild-type controls; however, renal blood flow was lower, whereas renal vascular resistance was augmented at baseline in Eln+/- mice. At 12 weeks, renal vascular resistance remained elevated while filtration fraction was higher in male Eln+/- relative to wild-type mice. Heterozygous mice showed isolated systolic hypertension that was evident only at nighttime. Acute salt loading with 6% dietary sodium increased daytime systolic blood pressure only in male Eln+/- mice, causing a rightward shift and blunted slope of the pressure-natriuresis curve. Renal interlobar artery basal tone and myogenic response to increasing intraluminal pressure at day 10 were similar, whereas they were augmented at day 30 and at 12 weeks old in Eln+/- mice, and normalized by the AT1R blocker, candesartan. Heterozygous mice also exhibited podocyte foot process damage that persisted even when blood pressure was normalized to wild-type levels with hydralazine. Thus, elastin insufficiency triggers structural defects and abnormal remodeling of renal vascular signaling involving AT1R-mediated vascular mechanotransduction and renal hyperfiltration with increased blood pressure sensitivity to dietary sodium contributing to systolic hypertension.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Elastin; Female; Humans; Hypertension; Kidney; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptor, Angiotensin, Type 1; Renal Elimination; Renal Insufficiency, Chronic; Signal Transduction; Sodium Chloride, Dietary; Tetrazoles; Vascular Resistance

Angiotensin (Ang) II plays an important role in fibrogenesis in various organs, including the lung. The aim of this study is to elucidate (i) the effects of Ang II on the expression of cytokines, growth factors or matrix proteins in normal human lung fibroblasts, and (ii) the inhibitory effects of an Ang II type 1 (AT1) receptor blocker, candesartan.. Normal human adult lung fibroblasts were cultured. Candesartan was added and the cells were incubated. All the cells in culture dishes were collected at day 0 and 2, and the cell numbers were counted using a Neubauer haemocytometer (Clay-Adams, Parsippany, NJ, USA). The cell proliferation rates at day 2 were calculated in comparison to those at day 0. Total cellular RNA was extracted for real-time quantitative PCR, or the culture supernatant was collected for either a Sircol assay or enzyme-linked immunosorbent assay (ELISA). Laser scanning confocal microscopy was used for analyzing the cells with and without prior exposure to candesartan. Comparisons between the means of multiple groups were analyzed by one-way analysis of variance (ANOVA) followed by Tukey's test or Games-Howell's test. Values of P < 0*05 were considered to be statistically significant.. Among the 12 fibrosis-associated cytokines and growth factors, mRNA expressions of interleukin (IL)-4, IL-7, and platelet-derived growth factor-D were significantly modulated by Ang II, and suppressed by candesartan. Soluble collagen and elastin levels were significantly elevated by Ang II, and suppressed by candesartan. Under confocal microscopy, the intracellular distribution of elastin was significantly increased by Ang II, and suppressed by candesartan.. These data indicate that Ang II promotes lung fibrosis by increasing the matrix formation, which was suppressed by AT1 receptor blocker.

Topics: Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Cell Proliferation; Cells, Cultured; Collagen; Cytokines; Elastin; Extracellular Matrix Proteins; Fibroblasts; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Lung; Microscopy, Confocal; RNA, Messenger; Tetrazoles