1. NF-kappaB activation is required for adaptive cardiac hypertrophy.
- Author
-
Zelarayan L, Renger A, Noack C, Zafiriou MP, Gehrke C, van der Nagel R, Dietz R, de Windt L, and Bergmann MW
- Subjects
- Angiotensin II metabolism, Animals, Apoptosis physiology, Cardiomegaly pathology, Disease Models, Animal, Female, Fibrosis, I-kappa B Proteins genetics, I-kappa B Proteins metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Myocardium metabolism, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Myosin Heavy Chains metabolism, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, Receptor, Angiotensin, Type 1 physiology, Signal Transduction physiology, Cardiomegaly metabolism, Cardiomegaly physiopathology, NF-kappa B metabolism, Sex Characteristics, Ventricular Remodeling physiology
- Abstract
Aims: We have previously shown that cardiac-specific inhibition of NF-kappaB attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-kappaB inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation., Methods and Results: Cardiac-restricted NF-kappaB inhibition was achieved by expression of a stabilized IkappaBalpha mutant (IkappaBalphaDeltaN) in cells with an active alpha-myosin heavy chain (alphaMHC) 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-kappaB inhibition. Amelioration of LV hypertrophy was associated with activation of NF-kappaB by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-kappaB 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-kappaB inhibition in an AngII-dependent genetic heart failure model (AT1-R(alphaMHC)) associated with significantly increased cardiac fibrosis in double AT1-R(alphaMHC)/TG mice., Conclusion: NF-kappaB inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-kappaB to be required for adaptive cardiac hypertrophy.
- Published
- 2009
- Full Text
- View/download PDF