NF-κB activation is required for adaptive cardiac hypertrophy

We have previously shown that cardiac-specific inhibition of NF-κB attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-κB inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation.

Cardiac-restricted NF-κB inhibition was achieved by expression of a stabilized IκBα mutant (IκBαΔN) in cells with an active α-myosin heavy chain (αMHC) promoter employing the Cre/lox technique. Upon low-gradient trans-aortic constriction (TAC, gradient 21 ± 3 mmHg), hypertrophy was induced in both male and female control mice after 4 weeks. At this time, LV hypertrophy was blocked in transgenic (TG) male but not female mice with NF-κB inhibition. Amelioration of LV hypertrophy was associated with activation of NF-κB by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-κB inhibition after 8 weeks TAC, demonstrated by decreased fractional shortening (FS) in both control and TG mice irrespective of gender. Similar results were obtained when TAC was performed with higher gradients (48 ± 4 mmHg). In TG mice, FS dropped to similar low levels over the same time course [FS sham, 29 ± 1% (mean ± SEM); FS control + 14 days TAC, 13 ± 3%; FS TG + 14 days TAC, 9 ± 5%]. Similarly, LV remodelling was accelerated by NF-κB inhibition in an AngII-dependent genetic heart failure model (AT1-R^αMHC) associated with significantly increased cardiac fibrosis in double AT1-R^αMHC/TG mice.

NF-κB inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-κB to be required for adaptive cardiac hypertrophy.