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

<strong><em>Background.</em></strong> 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<em> Wwp1</em> would alter the progression of LVPO induced HFpEF. <strong><em>Methods/Results</em></strong><em>.</em> LV echocardiography in mice with global <em>Wwp1</em> deletion (n=41; <em>Wwp1^-/-</em>) 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 (<em>Wwp1^+/+</em>; 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 <em>Wwp1^-/-</em> mice. With LVPO, the E/A ratio, an index of LV filling, was 3.97 + 0.46 in <em>Wwp1^+/+</em> but was 1.73 + 0.19 in the <em>Wwp1^-/-</em> group (p&lt;0.05). At the transcriptional level, mRNA for fibrillar collagens (types I and III) decreased by approximately 50% in <em>Wwp1^-/-</em> compared to the <em>Wwp1^+/+</em> group at 4 weeks post-LVPO (p&lt;0.05) and was paralleled by a similar difference in LV fibrillar collagen content as measured by histochemistry. Moreover, mRNA levels for determinants favoring ECM accumulation, such as transforming growth factor (TGF) increased with LVPO, but were lower in the <em>Wwp1^-/-</em> group. <strong><em>Summary.</em></strong> The absence of <em>Wwp1</em> reduced the development of LVH and subsequent progression to HFpEF. Modulating the WWP1 pathway could be a therapeutic target to alter the natural history of HFpEF.