0159 : Increased NOX4 Expression in Mice Knockdown of Angiopoietin-Like 2 Worsens Pressure Overload-Induced Cardiac Dysfunction but Preserves Vascular Endothelial Integrity

Angiopoietin-like 2 (angptl2) is a pro-inflammatory and pro-oxidative protein that induces endothelial dysfunction in mice. The impact of angptl2 on cardiac function is still unknown. We hypothesized that angptl2 could contribute to cardiac dysfunction and that knocking-down angptl2 would be protective against pressure overload. 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). TAC increased systolic pressure in the right carotid artery by 60% in WT, but only 28% in KD mice. In TAC-WT, but not in -KD mice, carotid and posterior cerebral arteries isolated from the highpressure right side displayed increased wall thickness, a remodeling associated with endothelial dysfunction. 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 heart weight / tibia length ratio, as well as a higher gene expression of hypertrophic remodeling molecular markers, (ANP, BNP, MyoHβ/MyoHα) when compared to TAC-WT mice. Cardiac function measured by Millar catheter also showed greater alteration of the left ventricular relaxation in TAC-KD mice (increased minimal and end diastolic pressures, 25% reduced relaxation rate), suggesting cardiac contractile dysfunction. Finally, we observed, only in hearts from TAC-KD mice, an increase in mRNA and protein expression of NOX4 which is known to produce H2O2, a deleterious hypertrophic stimulus in cardiomyocytes, but is a vasodilatory factor. 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. Up-regulation of NOX4 could, at least partly, contribute to these opposite effects in angptl2 KD mice.