Abstract 635: Inhibiting Reactive Apoptosis by Cardiac-specific Nix Ablation Prevents Decompensation of Pathological Hypertrophy
Background: Compensated pathological hypertrophy will inevitably remodel, leading to functional decompensation. Postulated mechanisms include cardiomyocyte dropout, changes in myocardial matrix, and altered cardiac metabolism. Transcriptional modulation of apoptosis-regulating Bcl2 family members is associated with myocardial hypertrophy, but a role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established.
Methods and Results: Proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gαq-dependent hypertrophies, was subjected to germ-line or cardiac-specific gene targeting (KO) using Cre-lox technology and conditional cardiac-specific overexpression (TG) using tetracycline suppressible bitransgenic system in mice. Conditional forced Nix expression in neonatal and adult hearts was well tolerated, but acted synergistically with the pro-hypertrophic Gαq transgene to increase cardiomyocyte apoptosis (TUNEL %: 0.8±0.1 in Gαq TG vs 7.8±0.6 in Gαq+Nix TG) and caused lethal cardiomyopathy with LV dilation (LVEDD mm: 3.7±0.2 vs 4.6±0.2) and depressed systolic function (% fractional shortening (%FS): 39±4 vs 23±4). Nix KO combined with Gαq TG significantly reduced cardiomyocyte apoptosis (TUNEL %: 4.8±0.2 in GαqTG+NixKO vs 8.4±0.5 in GαqTG), improved systolic function (LV%FS: 43±3 vs 27±3), attenuated LV remodeling (r/h:2.4±0.1 vs 4.0±0.6), and largely prevented lethality of the Gαq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice were subjected to transverse aortic constriction (TAC) (gradients: 89±4 vs 83±5 mmHg in controls, n=12 each, P=NS). In cardiac Nix KO, serial echocardiograms and terminal invasive hemodynamic studies at 9 weeks after TAC revealed significantly less LV dilation (LVEDD mm: 3.3±0.1 vs 3.8±0.2), maintained concentric remodeling (r/h:1.8±0.1 vs 2.3±0.3), and preserved function (%FS: 63±3 vs 51±4; +dP/dt40 mmHg/s: 11519±1211 vs 8499±399) as compared with controls.
Conclusions: Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, and suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.