The present study was to investigate the mRNA, protein expression and the activity of calcineurin in the hypertrophic heart, and to determine the effect of calcineurin inhibitor--cyclosporine A (CsA) on the regression of cardiac hypertrophy in renovascular hypertensive rats. Renovascular hypertension was induced by two kidney-one clip methods. Two months after the operation, cardiac hypertrophy was determined by histological analysis performed in some rats (2K1C-2M), then the rats were subdivided into 2 groups: (1) 3-month old two kidney-one clip group (2K1C-3M) with rats receiving 0.9% NaCl per day for one month, and (2) CsA-treated group with rats treated with CsA for one month. Sham-operated rats were used as control. The ratio of the left ventricular weight to tibial length (LVW/TL), the area of cardiac myocyte, mRNA and protein expression and the activity of calcineurin were determined. Both the LVW/TL and the cardiomyocyte area were significantly larger in 2K1C-2M and 2K1C-3M rats than in age-matched sham-operated rats. Treatment with CsA significantly attenuated the increase in the LVW/TL as well as the cardiomyocyte area. The mRNA, protein expression and the activity of calcineurin were significantly higher in 2K1C-2M and 2K1C-3M rats than those in the age-matched sham-operated rats, while the elevation of mRNA, protein expression and activity of calcineurin were significantly suppressed in the CsA-treated rats. In conclusion, calcineurin plays a role in the progression of cardiac hypertrophy in renovascular hypertensive rats. The inhibition of calcineurin can reverse cardiac hypertrophy.
Animals ; Calcineurin ; biosynthesis ; genetics ; metabolism ; Cyclosporine ; pharmacology ; Hypertension, Renovascular ; complications ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; etiology ; metabolism ; physiopathology ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Sprague-Dawley

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P<0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P<0.01). Compared with U, UH has lower HW/BW and LV/BW (P <0.05) and UE has normal HW/BW but lower LV/BW than U (P<0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal alpha-actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure- overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.
Actins/genetics/metabolism ; Anemia/*complications/drug therapy/metabolism ; Animals ; Atrial Natriuretic Factor/genetics/metabolism ; Erythropoietin/pharmacology/therapeutic use ; *Gene Expression ; Heart Ventricles/chemistry/drug effects/pathology ; Hydralazine/pharmacology/therapeutic use ; Hypertension/*complications/drug therapy/metabolism ; Hypertrophy, Left Ventricular/etiology/*genetics/metabolism ; Male ; Peptidyl-Dipeptidase A/genetics/metabolism ; RNA, Messenger/analysis/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta/genetics/metabolism ; Uremia/etiology/*genetics/metabolism

OBJECTIVE: To investigate the effect of atorvastatin on the expression of angiotensin converting enzyme 2 (ACE2) mRNA and its protein in hypertrophic myocardium in rats. METHODS: Suprarenal abdominal aortic coarctation was performed to create the pressure overload induced left ventricular hypertrophy model in rats. RESULTS: Rats were randomly divided into 5 groups: (1) normal control group (Group A); (2) normal control group treated with atorvastatin [(5 mg/(kg.dd), Group B]; (3) sham group (Group C); (4) atorvastatin given orally by gastric gavage for 4 weeks [5 mg/(kg.dd),Group D]; (5) vehicle group (Group E). Stained pathological section was observed under light microscope to measure cardiomyocyte diameter transversa and collagen volume fraction. ACE2 mRNA and its protein expression were detected by real-time RT-PCR and Western blot. Compared with Group A,B, and C, the left ventricular mass index, cardiomyocyte diameter transversa and collagen volume fraction in Group E increased statistically (P< 0.01), ACE2 mRNA and its protein expression also elevated remarkably (P< 0.01). Compared with Group E, the above mentioned indexes in Group D reduced significantly (P< 0.01). CONCLUSION ACE2 mRNA and its protein expression increase significantly in hypertrophic myocardium in rats; atorvastatin can attenuate cardiac hypertrophy due to pressure overload in rats effectively, and part of this anti-hypertrophy effect may be attributed to decrease ACE2 mRNA and protein expression.
Animals ; Aorta ; Atorvastatin ; Heptanoic Acids ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Hypertrophy, Left Ventricular ; etiology ; metabolism ; Ligation ; Male ; Peptidyl-Dipeptidase A ; biosynthesis ; genetics ; Pyrroles ; pharmacology ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley