Abstract 15623: Angiopoietin Like-2 Knockdown Worsens Pressure Overload-Induced Cardiac Dysfunction Despite Preserving Vascular Endothelial Integrity in Mice
Background: High circulating levels of angiopoietin-like 2 (angptl2), a pro-inflammatory protein, have been associated with obesity, diabetes and atherosclerosis. In mice, angptl2 induces vascular inflammation and endothelial dysfunction, but the impact of angptl2 on cardiac function is still unknown. Since mechanical stress has been shown to promote angptl2 expression and tissue remodeling, we hypothesized that angptl2 could contribute to cardiac dysfunction and that knocking down angptl2 would be protective against pressure overload.
Methods/Results: We investigated both cardiac and vascular endothelial functions in angptl2 knockdown mice (KD) versus wild-type (WT) littermates, in response to a 6-week pressure overload induced by transverse aortic constriction (TAC). While peripheral blood pressure was not affected by TAC, systolic pressure in the right carotid artery was increased by 60 % in WT, but only by 28 % in KD mice (p<0.05 vs. WT, n=8). In WT, but not in KD mice, carotid and posterior cerebral arteries isolated from the high-pressure right side displayed increased wall thickness (p<0.05 vs. sham), a remodeling associated with endothelial dysfunction. Indeed, in isolated pressurized cerebral arteries, maximal acetylcholine-mediated dilation was reduced by TAC in WT mice (from 33±4 to 16±3%; p<0.05, n=12), but not in KD mice (from 27±2 to 22±2%, n=12). In contrast, and contrary to our hypothesis, TAC induced a more severe cardiac remodeling in KD than in WT mice: TAC KD mice displayed a greater (p<0.05 vs. WT) heart weight / tibia length ratio, as well as a higher (p<0.05, n=6) gene expression of hypertrophic remodeling molecular markers, such as ANP, BNP and MyoHβ/MyoHα ratio when compared to TAC WT mice. Finally, cardiac function measured by Millar pressure catheter showed greater alteration of the left ventricular relaxation in TAC KD mice, as evidenced by increased minimal and end diastolic pressures (p<0.05 vs. WT), together with a 25% reduced (p<0.05 vs. WT, n=6) relaxation rate.
Conclusion: This is the first demonstration that angptl2 knockdown paradoxically worsens cardiac hypertrophy and contractile dysfunction induced by pressure overload, contrasting with the preserved arterial wall structure and endothelial integrity.
Author Disclosures: C. Martel: None. A. Raignault: None. C. Yu: None. M. Gillis: None. N. Duquette: None. N. Thorin-Trescases: None. C. Des Rosiers: None. E. Thorin: None.
- © 2014 by American Heart Association, Inc.