angiotensinogen and Hypertrophy--Right-Ventricular

We have recently reported that transgenic (mRen2)27 rats (Ren2 rats) exhibit pulmonary arterial hypertension (PAH), which is, in part, mediated by oxidative stress. Since 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exhibit beneficial vascular effects independent of cholesterol synthesis, we hypothesized that rosuvastatin (RSV) treatment ameliorates PAH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Six-week-old male Ren2 and Sprague-Dawley rats received RSV (10 mg x kg(-1) x day(-)1 ip) or vehicle for 3 wk. After treatment, right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. To evaluate treatment effects on pulmonary arteriole remodeling, morphometric analyses were performed to quantitate medial thickening and cell proliferation, whereas whole lung samples were used to quantitate the levels of 3-nitrotyrosine, superoxide, stable nitric oxide (NO) metabolites [nitrates and nitrites (NO(x))], and expression of NO synthase isoforms. In the Ren2 rat, RVSP is normal at 5 wk of age, PAH develops between 5 and 7 wk of age, and the elevated pressure is maintained with little variation through 13 wk. At 8 wk of age, left ventricular function and blood gases were normal in the Ren2 rat. Ren2 rats exhibited elevations in medial hypertrophy due to smooth muscle cell proliferation, 3-nitrotyrosine, NO(x), NADPH oxidase activity, and endothelial NO synthase expression compared with Sprague-Dawley rats. RSV significantly blunted the increase in RVSP but did not reduce MAP in the Ren2 rat; additionally, RSV significantly attenuated the elevated parameters examined in the Ren2 rat. These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation.

Topics: Angiotensinogen; Animals; Fluorobenzenes; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Peptidyl-Dipeptidase A; Pulmonary Artery; Pyrimidines; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Angiotensin, Type 1; Rosuvastatin Calcium; Sulfonamides; Ventricular Function, Left; Ventricular Function, Right

The present study evaluated the importance of ovarian functions and the renin-angiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevated renin mRNA levels. Gene expression levels of angiotensinogen, TGF-beta1, and endothelin-1 in the hypertrophied RV also increased, but to the less degree than did the renin mRNA. To investigate beneficial effects of estrogen or enalapril on progression of the pulmonary hypertension and RV hypertrophy, histological changes of the lung and heart were examined. Sham-MCT female rats showed histological changes indicating pulmonary hypertension without RV hypertrophy. In contrast, Ovx-MCT rats showed marked RV hypertrophy with pathological changes, denoting severe pulmonary and myocardial injuries. Estrogen-or enalapril-treated Ovx-MCT rats did not show RV hypertrophy, and showed remarkably ameliorated ultrastructural changes in the lung and RV. These results from this rat model suggest that both estrogen and inhibition of the renin-angiotensin system have protective functions against the development of the pulmonary hypertension and cardiac remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Body Weight; Densitometry; Disease Progression; Enalapril; Endothelin-1; Estrogens; Female; Hypertrophy, Right Ventricular; Male; Microscopy, Electron; Monocrotaline; Ovariectomy; Rats; Rats, Sprague-Dawley; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sex Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

The renin angiotensin system plays an important role in the development of pulmonary artery remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary hypertension as may occur in patients with COPD. Several polymorphisms of genes encoding for components of the renin angiotensin system such as the M235T polymorphism in the angiotensinogen gene, the 287-base-pair insertion (I)/deletion (D) polymorphism at intron 16 of the ACE gene, and the A1166C polymorphism in the angiotensin II type 1 receptor gene have been associated with an increased risk of cardiovascular diseases. With respect to the pulmonary circulation, only limited data exist on possible associations between polymorphisms of these genes and pulmonary hypertension and/or right ventricular hypertrophy. The objective of the present study was to investigate a possible relationship between polymorphisms of the renin angiotensin system and electrocardiographic evidence of right ventricular hypertrophy in patients with COPD. We therefore determined the angiotensinogen (M235T), angiotensin converting enzyme (I/D), and angiotensin II type 1 receptor (A1166C) genotypes in 87 patients with severe COPD and correlated these data with electrocardiographic parameters of right ventricular hypertrophy. Thirty-one patients (36%) of 87 patients with COPD showed electrocardiographic evidence of right ventricular hypertrophy. In the male, but not in the female, subgroup, the angiotensin-converting enzyme DD genotype was negatively associated with electrocardiographic evidence of right ventricular hypertrophy (male: chi2 = 3.8, p = 0.05; female: chi2 = 0.05, p = 0.82). We found no associations between the investigated polymorphisms in the angiotensinogen and angiotensin II type 1 receptor genes and electrocardiographic evidence of right ventricular hypertrophy.

Topics: Aged; Angiotensinogen; DNA Transposable Elements; Electrocardiography; Female; Gene Deletion; Gene Frequency; Genotype; Humans; Hypertrophy, Right Ventricular; Lung Diseases, Obstructive; Male; Middle Aged; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sex Characteristics