Inhibition of NF-kappaB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats.
The transcription factor nuclear factor (NF)-kappaB 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-kappaB cascade with pyrrolidine dithiocarbamate (PDTC) in spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) affected hypertrophy. We measured NF-kappaB signaling components [NF-kappaB translocation, IkappaBalpha, p65, mRNA and protein levels, and IkappaB kinase-beta (IKKbeta) activity] at 12 and 36 wk in WKYs and SHRs and at 10 wk in PDTC-treated rats (n = 9). NF-kappaB 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-kappaB 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-kappaB 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-kappaB 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-kappaB activity (169.71 +/- 5.70 to 97.29 +/- 3.65). Our data suggest that 1) cardiac hypertrophy in SHRs is partly due to NF-kappaB activation, 2) inhibition of NF-kappaB activity by PDTC parallels regression of hypertrophy, and 3) regression of hypertrophy is partly due to inhibition of NF-kappaB activity, independent of hypertension. The relationship between NF-kappaB activity and cardiac remodeling is causal, not coincidental.
Gupta
Sudhiranjan
S
Dept. of Molecular Cardiology, NB 50, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
Young
David
D
Sen
Subha
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D018450:Disease Progression; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D011759:Pyrrolidines; D013859:Thiocarbamates; D014665:Vasodilator Agents; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D006830:Hydralazine; D002216:Captopril