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Inhibition of NF-B induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats

Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio

Submitted 27 January 2005 ; accepted in final form 1 March 2005

The transcription factor nuclear factor (NF)-B plays a leading role in cardiac hypertrophy associated with heart failure, but whether it is involved 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 hypertrophy. We measured NF-B signaling components [NF-B translocation, IB, p65, mRNA and protein levels, and IB kinase- (IKK) activity] at 12 and 36 wk in WKYs and SHRs and at 10 wk in PDTC-treated rats (n = 9). NF-B activation was also evaluated in rats treated for 10 wk with captopril or hydralazine alone or with either drug plus PDTC. All components were increased in SHRs compared with WKYs. After PDTC treatment, NF-B activity was inhibited, and heart weight-to-body weight ratio in SHRs 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 mmHg) 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.

nuclear factor-B; pyrrolidine dithiocarbamate; captopril; hydralazine

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