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B Induces Regression of Cardiac Hypertrophy, Independent of Blood Pressure Control, in Spontaneously Hypertensive Rats
1 Molecular Cardiology, NB 50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: sens{at}ccf.org.
The transcription factor NF-
B plays a leading role in cardiac hypertrophy with heart failure, but whether its involvement in cardiac mass reduction is not known. We evaluated whether inhibiting the NF-B cascade with pyrrolidine dithiocarbamate (PDTC) in spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) affected hypertophy. We measured NF-kB signaling components (NF-B translocation, IB
, p65; mRNA and protein levels, and IKK
activity) at 12 and 36 weeks in WKYs and SHRs and at 10 weeks in PDTC-treated rats (n=9). NF-B activation was also evaluated in rats treated for 10 weeks with captopril or hydralazine alone or either drug plus PDTC. All components were increased in SHRs compared with WKYs. After PDTC treatment, NF-B activity inhibited; heart weight:body weight ratio in SHR was significantly attenuated (3.52 ± 0.04 to 3.32 ± 0.05 mg/kg). Captopril treatment significantly reduced cardiac mass (3.5 vs 3.05 mg/kg; n = 9) and inhibited NF-B activity (169.71 ± 5.70 to 106.7 ± 12.44). Hydralazine had no effect on cardiac mass (3.5 vs 3.42 mg/kg) or NF-B activity (169.71 ± 5.70 to 155.52 ± 6.11). Hydralazine plus PDTC reduced blood pressure (191.16 ± 1.7 to 158.5 ±2.36 mm Hg) and inhibited NF-B activity (169.71 ± 5.70 to 97.29 ± 3.65). Our data suggest that: (1) cardiac hypertrophy in SHRs is partly due to NF-B activation, (2) inhibition of NF-B activity by PDTC parallels regression of hypertrophy, and (3) regression of hypertrophy is partly due to inhibition of NF-B activity, independent of hypertension. The relationship between NF-B activity and cardiac remodeling is causal, not coincidental.
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