Ubiquitin Ligase Wwp1 Gene Deletion Attenuates Diastolic Dysfunction in Pressure Overload Hypertrophy

Background. Heart failure with a preserved left ventricular (LV) ejection fraction (HFpEF) often arises from a prolonged LV pressure overload (LVPO) and accompanied by abnormal extracellular matrix (ECM) accumulation. The E3 ubiquitin ligase WWP1 is a fundamental determinant ECM turnover. We tested the hypothesis that genetic ablation of Wwp1 would alter the progression of LVPO induced HFpEF. Methods/Results. LV echocardiography in mice with global Wwp1 deletion (n=41; Wwp1-/-) was performed at 12 weeks of age (Baseline) and then at 2 and 4 weeks following LVPO (transverse aortic banding) or surgery without LVPO induction. Age-matched wild type mice (Wwp1+/+; n=33) underwent identical protocols. LV EF remained constant and unchanged with LVPO and LV mass increased in both groups but was lower in the Wwp1-/- mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 + 0.46 in Wwp1+/+ but was 1.73 + 0.19 in the Wwp1-/- group (p<0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in Wwp1-/- compared to the Wwp1+/+ group at 4 weeks post-LVPO (p