Abstract 16267: NADPH Oxidase Nox4 Up-regulation Contributes to the Worsening of Pressure Overload-induced Cardiac Dysfunction in Angiopoeitin-like 2 Knockdown Mice
Background: Angiopoietin-like 2 (angptl2) is a circulating protein promoting vascular inflammation and endothelial dysfunction in mice, but little is known on its impact on cardiac function. Our previous results suggest that knocking down angptl2 in mice (KD) worsens pressure overload-induced cardiac dysfunction while preserving cerebral artery structure and endothelial function. As NADPH oxidase NOX4 is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes but also a vasodilatory factor, we hypothesized that increased expression of NOX4 contributes to the aggravated cardiac dysfunction observed in KD mice.
Methods/Results: Cardiac function was measured in vivo by Millar catheter in KD mice versus their wild-type (WT) littermates in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). Concomitantly to a worsened cardiac remodeling and an aggravated cardiac dysfunction compared to WT-TAC mice, only KD-TAC mice displayed an increase in cardiac mRNA and protein expression of NOX4 (p<0.05 vs. WT, n=8). To specifically decrease cardiac NOX4 expression, we performed, two weeks after TAC surgery, a single i.v. injection of cardiac specific associated adenovirus AAV9 expressing a NOX4-targeted shRNA or a scrambled shRNA. In KD-TAC mice, the AAV9-shNOX4 limited cardiac hypertrophy as evidenced by a smaller heart/tibia ratio (Table, * p<0.05). Moreover, cardiac function in KD-TAC-AAV9-shNOX4 mice was partly prevented by maintaining contraction and relaxation maximal velocities and by limiting the abnormal rise of minimal pressure and end diastolic pressure caused by TAC (Table, * p<0.05).
Conclusion: Angptl2 knockdown worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload: cardiac up-regulation of NOX4 could contribute to these deleterious effects in angptl2 KD mice.
Author Disclosures: C. Martel: None. A. Raignault: None. C. Yu: None. M. Gillis: None. M. Mamarbachi: None. N. Bousette: None. N. Duquette: None. N. Thorin-Trescases: None. C. Des Rosiers: None. E. Thorin: None.
- © 2015 by American Heart Association, Inc.