3-HMG-Coenzyme A reductase inhibition and extracellular matrix gene expression in the pressure-overloaded rat heart
ABSTRACT The purpose of this study was to determine whether 3-HMG-Coenzyme A (HMG-CoA) reductase inhibition would attenuate the early pressure overload-induced activation of extracellular matrix genes in the left ventricle (LV) of the heart. Sprague-Dawley rats were randomized to 1 of 4 treatment groups: sham-operation+vehicle (SH-V), aortic constriction+vehicle (AC-V), AC+rosuvastatin (RSV, 2 mg/kg; AC-LO), and AC+RSV (10 mg/kg; AC-HI). Rats were injected with normal NaCl (V) or RSV once daily, beginning 1 day before surgery, and killed 1 or 3 days after surgery. Hemodynamic measurements were made in the open-chest anesthetized state. LV levels of transforming growth factor beta1 (TGF-beta1), procollagen 1 (C1), and fibronectin (FN) mRNA were measured by Northern blotting. AC induced a approximately 25% increase in LV weight after 3 days that was not altered by RSV treatment. LV expression of TGF-beta1, C1, and FN mRNA was approximately 2-fold, approximately 2.5-fold, and approximately 5-fold greater, respectively, in hearts of AC-V compared to SH-V rats 3 days post-operation, and was not significantly decreased by either dose of RSV. Inhibition of HMG-CoA reductase does not attenuate the pronounced aortic constriction-induced increases in the early expression of TGF-beta1, C1, and FN in this model of acute pressure overload of the rat heart.
SourceAvailable from: Andrei Alkmim Teixeira[Show abstract] [Hide abstract]
ABSTRACT: Among hypertensive patients, cardiovascular disease morbidity is common, even in those who are adequately treated. New pharmacological strategies to mitigate the burden of arterial hypertension are needed. This 12-month, randomized, double-blind placebo-controlled study investigated the effect of statin (fluvastatin) treatment on ambulatory blood pressure (ABP), exercise blood pressure (EBP), myocardial structure, endothelial function and insulin resistance in 50 hypertensive patients. At baseline, the groups were comparable in terms of demographic characteristics, ABP, EBP, endothelial function and homeostasis model assessment of insulin resistance (HOMA-IR). At the end of the study, there was no difference between groups in terms of resting systolic blood pressure. However, maximum systolic EBP was lower in the treatment group than in the placebo group (175 ± 18 vs 192 ± 23 mm Hg, P<0.05), as was left ventricular mass index (LVMI; 82 ± 15 vs 100 ± 23, P<0.05), and HOMA-IR index was lower after fluvastatin treatment (2.77 ± 1.46 vs 3.33 ± 1.73, P<0.05). Changes in lipid profile were not correlated with blood pressure, endothelial function, LVMI or HOMA-IR data. In hypertensive patients, fluvastatin can improve maximum systolic EBP, myocardial remodelling and insulin resistance, independently of lipid profile variations and endothelial function.Journal of human hypertension 08/2011; 25(8):492-9. DOI:10.1038/jhh.2010.87 · 2.69 Impact Factor
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ABSTRACT: Gradual occlusion (O) of the swine left circumflex coronary artery (LCX) with an ameroid occluder results in complete O within 3 weeks, collateral vessel development, and compensatory hypertrophy. The purpose of this investigation was to determine the independent and combined effects of O and exercise training (E) on gene expression in the swine heart. Adult Yucatan miniature swine were assigned to one of the following groups (n=6-9/group): sedentary control (S), exercise-trained (E), sedentary swine subjected to LCX occlusion (SO), and exercise-trained swine with LCX occlusion (EO). Exercise consisted of progressive treadmill running conducted 5 d/wk for 16 weeks. Gene expression was studied in myocardium isolated from the collateral-dependent left ventricle free wall (LV) and the collateral-independent septum (SEP) by RNA blotting. E and O each stimulated cardiac hypertrophy independently (p<0.001) with no interaction. O but not E increased atrial natriuretic factor expression in the LV, but not in the SEP. E decreased the expression of beta-myosin heavy chain in the LV, but not in the SEP. E retarded the expression of collagen III mRNA in SEP; but not in the LV. Exercise training and coronary artery occlusion each stimulate cardiac hypertrophy independently and induce different patterns of gene expression.Molecular and Cellular Biochemistry 02/2007; 294(1-2):87-96. DOI:10.1007/s11010-006-9248-x · 2.39 Impact Factor
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ABSTRACT: To determine the effects of hawthorn (Crataegus oxycantha) on left ventricular remodeling and function in pressure overload-induced heart failure in an animal model. Randomized, parallel, dose-ranging animal study. University research facility. Seventy-four male Sprague-Dawley rats; 44 were included in the final analysis. Rats underwent a sham operation or aortic constriction. Rats subjected to the sham operation were treated with vehicle (10% agar-agar), and those subjected to aortic constriction were treated with vehicle or hawthorn (C. oxycantha special extract WS 1442) 1.3, 13, or 130 mg/kg for 5 months. Rats and their hearts were weighed, and echocardiographic measurements were performed at baseline and at 2, 3, 4, and 5 months after aortic constriction. Protein expression for markers of fibrosis and for atrial natriuretic factor was also measured. Aortic constriction increased the left ventricular:body weight ratio by 53% in vehicle-treated rats; Hawthorn treatment did not significantly affect the aortic constriction-induced increase in this ratio. Left ventricular volumes and dimensions at systole and diastole significantly increased 5 months after aortic constriction compared with baseline in rats given vehicle (> 20% increase, p<0.05) but not in those given hawthorn 130 mg/kg (< 10% increase). After aortic constriction, the velocity of circumferential shortening significantly decreased in the vehicle group but not in the medium- or high-dose groups. In the aortic constriction-vehicle group, the induced increases in messenger RNA expression for atrial natriuretic factor (approximately 1000%) and fibronectin (approximately 80%) were significantly attenuated by high-dose hawthorn treatment by approximately 80% and 50%, respectively. Hawthorn treatment exhibited modest beneficial effects on cardiac remodeling and function during long-term, pressure overload-induced heart failure in rats.Pharmacotherapy 06/2009; 29(6):639-48. DOI:10.1592/phco.29.6.639 · 2.20 Impact Factor